Pharmaceutical compositions and methods for use

ABSTRACT

The present invention relates to aryl olefinic azacyclic compounds and aryl acetylenic azacyclic compounds, including pyridyl olefinic cycloalkylamines and pyridyl acetylenic cycloalkylamines. The present invention also relates to prodrug derivatives of the compounds of the present invention.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.09/845,526, filed Apr. 30, 2001, the disclosure of which is incorporatedby reference herein in its entirety, which is a continuation-in-part ofU.S. application Ser. No. 09/431,700, filed Nov. 1, 1999, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to pharmaceutical compositions,particularly pharmaceutical compositions incorporating compounds thatare capable of affecting nicotinic cholinergic receptors. Moreparticularly, the present invention relates to compounds capable ofactivating nicotinic cholinergic receptors, for example, as agonists ofspecific nicotinic receptor subtypes. The present invention also relatesto methods for treating a wide variety of conditions and disorders,particularly conditions and disorders associated with dysfunction of thecentral and autonomic nervous systems.

Nicotine has been proposed to have a number of pharmacological effects.See, for example, Pullan et al., N. Engl. J. Med. 330:811 (1994).Certain of those effects may be related to effects upon neurotransmitterrelease. See, for example, Sjak-shie et al., Brain Res. 624:295 (1993),where neuroprotective effects of nicotine are proposed. Release ofacetylcholine and dopamine by neurons upon administration of nicotinehas been reported by Rowell et al., J. Neurochem. 43:1593 (1984); Rapieret al., J. Neurochem. 50:1123 (1988); Sandor et al., Brain Res. 567:313(1991) and Vizi, Br. J. Pharmacol. 47:765 (1973). Release ofnorepinephrine by neurons upon administration of nicotine has beenreported by Hall et al., Biochem. Pharmacol. 21:1829 (1972). Release ofserotonin by neurons upon administration of nicotine has been reportedby Hery et al., Arch. Int. Pharmacodyn. Ther. 296:91 (1977). Release ofglutamate by neurons upon administration of nicotine has been reportedby Toth et al., Neurochem Res. 17:265 (1992). Confirmatory reports andadditional recent studies have included the modulation in the CentralNervous System (CNS) of glutamate, nitric oxide, GABA, takykinins,cytokines and peptides (reviewed in Brioni et al., Adv. Pharmacol.37:153 (1997)). In addition, nicotine reportedly potentiates thepharmacological behavior of certain pharmaceutical compositions used forthe treatment of certain disorders. See, for example, Sanberg et al.,Pharmacol. Biochem. & Behavior 46:303 (1993); Harsing et al., J.Neurochem. 59:48 (1993) and Hughes, Proceedings from Intl. Symp. Nic.S40 (1994). Furthermore, various other beneficial pharmacologicaleffects of nicotine have been proposed. See, for example, Decina et al.,Biol. Psychiatry 28:502 (1990); Wagner et al., Pharmacopsychiatry 21:301(1988); Pomerleau et al., Addictive Behaviors 9:265 (1984); Onaivi etal., Life Sci. 54(3):193 (1994); Tripathi et al., J. Pharmacol. Exp.Ther. 221:91(1982) and Hamon, Trends in Pharmacol. Res. 15:36 (1994).

Various nicotinic compounds have been reported as being useful fortreating a wide variety of conditions and disorders. See, for example,Williams et al., Drug News Perspec. 7(4):205 (1994); Arneric et al., CNSDrug Rev. 1(1): 1 (1995); Arneric et al., Exp. Opin. Invest. Drugs5(1):79 (1996); Bencherif et al., J. Pharmacol. Exp. Ther. 279:1413(1996); Lippiello et al., J. Pharmacol. Exp. Ther. 279:1422 (1996);Damaj et al., J. Pharmacol. Exp. Ther. 291:390 (1999); Chiari et al.,Anesthesiology 91:1447 (1999); Lavand'homme and Eisenbach,Anesthesiology 91:1455 (1999); Holladay et al., J. Med. Chem 40(28):4169 (1997); Bannon et al., Science 279: 77 (1998); PCT WO 94/08992, PCTWO 96/31475, PCT WO 96/40682, and U.S. Pat. No. 5,583,140 to Bencherifetal., U.S. Pat. No. 5,597,919 to Dull et al., U.S. Pat. No. 5,604,231 toSmith et al. and U.S. Pat. No. 5,852,041 to Cosford et al. Nicotiniccompounds are reported as being particularly useful for treating a widevariety of CNS disorders. Indeed, a wide variety of compounds have beenreported to have therapeutic properties. See, for example, U.S. Pat. No.5,1871,166 to Kikuchi et al., U.S. Pat. No. 5,672,601 to Cignarella, PCTWO 99/21834 and PCT WO 97/40049, UK Patent Application GB 2295387 andEuropean Patent Application 297,858.

CNS disorders are a type of neurological disorder. CNS disorders can bedrug induced; can be attributed to genetic predisposition, infection ortrauma; or can be of unknown etiology. CNS disorders compriseneuropsychiatric disorders, neurological diseases and mental illnesses,and include neurodegenerative diseases, behavioral disorders, cognitivedisorders and cognitive affective disorders. There are several CNSdisorders whose clinical manifestations have been attributed to CNSdysfunction (i.e., disorders resulting from inappropriate levels ofneurotransmitter release, inappropriate properties of neurotransmitterreceptors, and/or inappropriate interaction between neurotransmittersand neurotransmitter receptors). Several CNS disorders can be attributedto a deficiency of choline, dopamine, norepinephrine and/or serotonin.Relatively common CNS disorders include pre-senile dementia (early-onsetAlzheimer's disease), senile dementia (dementia of the Alzheimer'stype), micro-infarct dementia, AIDS-related dementia, Creutzfeld-Jakobdisease, Pick's disease, Parkinsonism including Parkinson's disease,progressive supranuclear palsy, Huntington's chorea, tardive dyskinesia,hyperkinesia, mania, attention deficit disorder, anxiety, dyslexia,schizophrenia, depression, obsessive-compulsive disorders and Tourette'ssyndrome.

It would be desirable to provide a useful method for the prevention andtreatment of a condition or disorder by administering a nicotiniccompound to a patient susceptible to or suffering from such a conditionor disorder. It would be highly beneficial to provide individualssuffering from certain disorders (e.g., CNS diseases) with interruptionof the symptoms of those disorders by the administration of apharmaceutical composition containing an active ingredient havingnicotinic pharmacology and which has a beneficial effect (e.g., upon thefunctioning of the CNS), but which does not provide any significantassociated side effects. It would be highly desirable to provide apharmaceutical composition incorporating a compound which interacts withnicotinic receptors, such as those which have the potential to effectthe functioning of the CNS, but, when employed in an amount sufficientto effect the functioning of the CNS, does not significantly effectthose receptor subtypes which have the potential to induce undesirableside effects (e.g., appreciable activity at cardiovascular and skeletalmuscle sites).

SUMMARY OF THE INVENTION

The present invention relates to aryl olefinic azacyclic compounds andaryl acetylenic azacyclic compounds, including pyridyl olefiniccycloalkylamines and pyridyl acetylenic cycloalkylamines. The presentinvention also relates to prodrug derivatives of the compounds of thepresent invention. The present invention also relates to methods ofsynthesizing compounds of the present invention. Exemplary compounds ofthe present invention include (S)-5-(pyrrolidin-2-ylethynyl)pyrimidine,(S)-3-(pyrrolidin-2-ylethynyl)pyridine,(S)-3-isopropoxy-5-(pyrrolidin-2-ylethynyl)pyridine,(S)-3-phenyl-5-(pyrrolidin-2-ylethynyl)pyridine,(S)-3-(4-methoxyphenoxy)-5-(pyrrolidin-2-ylethynyl)pyridine,(S)-3-cyclopentyloxy-5-(pyrrolidin-2-ylethynyl)pyridine,(S)-3-cyclohexyloxy-5-(pyrrolidin-2-ylethynyl)pyridine,(S)-3-(4-(pyrrolidine-1-sulfonyl)phenoxy)-5-(pyrrolidin-2-ylethynyl)pyridine,(S)-3-(3-pyridyloxy)-5-(pyrrolidin-2-ylethynyl)pyridine,(S)-3-(pyrrolidin-2-ylethynyl)-5-(tetrahydropyran-4-yloxy)pyridine,(S)-3-(3,5-dihydroxy)phenoxy-5-(pyrrolidin-2-ylethynyl)pyridine,(S)-N-(2-(5-pyrrolidin-2-ylethynylpyridin-3-yloxy)ethyl)benzamide,(S)-3-(pyrrolidin-2-ylethynyl)-5-(3-methylsulfonylphenoxy)pyridine,(E,S)-3-(4-hydroxyphenoxy)-5-(pyrrolidin-2-ylvinyl)pyridine,(E,S)-3-cyclopentyloxy-5-(pyrrolidin-2-ylvinyl)pyridine. The compoundsof the present invention function as agonists and bind specifically tocertain nicotinic receptors.

The present invention also relates to methods for the prevention ortreatment of a wide variety of conditions or disorders, and particularlythose disorders characterized by dysfunction of nicotinic cholinergicneurotransmission including disorders involving neuromodulation ofneurotransmitter release, such as dopamine release. The presentinvention also relates to methods for the prevention or treatment ofdisorders, such as central nervous system (CNS) disorders, which arecharacterized by an alteration in normal neurotransmitter release. Thepresent invention also relates to methods for the treatment of certainconditions (e.g., a method for alleviating pain). The methods involveadministering to a subject an effective amount of a compound of thepresent invention. As such, the present invention relates to a methodfor using the compounds of the present invention for the manufacture ofpharmaceutical compositions for the treatment of a wide variety ofdiseases and disorders.

The present invention, in another aspect, relates to a pharmaceuticalcomposition comprising an effective amount of a compound of the presentinvention. Such a pharmaceutical composition incorporates a compoundwhich, when employed in effective amounts, has the capability ofinteracting with relevant nicotinic receptor sites of a subject, andhence has the capability of acting as a therapeutic agent in theprevention or treatment of a wide variety of conditions and disorders,particularly those disorders characterized by an alteration in normalneurotransmitter release. Preferred pharmaceutical compositions comprisecompounds of the present invention.

The pharmaceutical compositions of the present invention are useful forthe prevention and treatment of disorders, such as CNS disorders, whichare characterized by an alteration in normal neurotransmitter release.The pharmaceutical compositions provide therapeutic benefit toindividuals suffering from such disorders and exhibiting clinicalmanifestations of such disorders in that the compounds within thosecompositions, when employed in effective amounts, have the potential to:(i) exhibit nicotinic pharmacology and affect relevant nicotinicreceptors sites (e.g., act as a pharmacological agonist to activatenicotinic receptors), and/or (ii) modulate neurotransmitter secretionand thus prevent and suppress the symptoms associated with thosediseases. In addition, the compounds are expected to have the potentialto fulfill the following results for the patient: (i) to alter thenumber of nicotinic cholinergic receptors of the brain of the patient,(ii) to exhibit neuroprotective effects and (iii) to result in noappreciable adverse side effects when administered in effectiveamounts—side effects such as significant increases in blood pressure andheart rate, significant negative effects upon the gastrointestinaltract, and significant effects upon skeletal muscle. The pharmaceuticalcompositions of the present invention are believed to be safe andeffective with regards to prevention and treatment of a wide variety ofconditions and disorders.

The foregoing and other aspects of the present invention are explainedin detail in the detailed description and examples set forth below.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention include compounds of the formula:

where Q is defined hereinafter; and each of X, X′, X″, Y′ and Y″ areindividually nitrogen, nitrogen bonded to oxygen (e.g., an N-oxide orN—O functionality) or carbon bonded to a substituent speciescharacterized as having a sigma m value greater than 0, often greaterthan 0.1, and generally greater than 0.2, and even greater than 0.3;less than 0 and generally less than −0.1; or 0; as determined inaccordance with Hansch et al., Chem. Rev. 91:165 (1991). When any of X,X′, X″, Y′ and Y″ are carbon bonded to a substituent species, thosesubstituent species typically have a sigma m value between about −0.3and about 0.75, frequently between about −0.25 and about 0.6; and eachsigma m value individually can be 0 or not equal to zero. Preferably,less than 4, more preferably less than 3, and most preferably 1 or 2 ofX, X′, X″, Y′ and Y″ are nitrogen or nitrogen bonded to oxygen. Inaddition, it is highly preferred that not more than 1 of X, X′, X″, Y′and Y″ be nitrogen bonded to oxygen; and it is preferred that if one ofthose species is nitrogen bonded to oxygen, that species is X″.Typically, X′ is CH, CR′ or COR′, where R′ preferably is alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl, any of which may befurther substituted as described hereinbelow. Most preferably, X″ isnitrogen. In certain preferred circumstances, both X′ and X″ arenitrogen. Typically, X, Y′ and Y″ each are carbon bonded to asubstituent species, and it is typical that X, Y′ and Y″ each are carbonbonded to a substituent species such as hydrogen. Typically, X is CH andY′ is CH.

The substituents of either X, X′, X″, Y′ and Y″ (when each respective X,X′, X″, Y′ and Y″ is carbon) can include alkyl, substituted alkyl,alkenyl, substituted alkenyl, heterocyclyl, substituted heterocyclyl,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkylaryl,substituted alkylaryl, arylalkyl, substituted arylalkyl, halo (e.g., F,Cl, Br, or I), —OR′, —NR′R″, —CF₃, —CN, —NO₂, —C₂R′, —SR′, —N₃,—C(═O)NR′R″, —NR′C(═O)R″, —C(═O)R′, —C(═O)OR′, —OC(═O)R′,—O(CR′R″)_(r)C(═O)R′, —O(CR′R″)_(r)NR′R″—O(CR′R″)_(r)NR″C(═O)R′,—O(CR′R″)_(r)NR″SO₂R′, —OC(═O)NR′R″, —NR′C(═O)O R″, —SO₂R′, —SO₂NR′R″,and —NR′SO₂R″, where R′ and R″ are individually hydrogen, lower alkyl,cycloalkyl, heterocyclyl, or an aromatic group-containing species and ris an integer from 1 to 6. R′ and R″ can together form a cycloalkylfunctionality. Representative aromatic group-containing species includephenyl, benzyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyland quinolinyl. Other representative aromatic ring systems are set forthin Gibson et al., J. Med. Chem. 39:4065 (1996). When either R′ or R″ isa non-hydrogen substituent species, it may be further substituted, oneor more times, by non-hydrogen substituent species, as describedhereinbefore. Adjacent substituents of X, X′, Y″, X″ and Y′ (whenadjacent X, X′, Y″, X″ and Y′ each are carbon bonded to a respectivesubstituent component) can combine to form one or more saturated orunsaturated, substituted or unsubstituted carbocyclic or heterocyclicrings containing, but not limited to, ether, acetal, ketal, amine,ketone, lactone, lactam, carbamate, or urea functionalities.

B′ is a substituted or unsubstituted two carbon bridging species; andtypically can be acetylenic or ethylenic, preferably acetylenic. Thatis, B′ can be selected from —CC— or —CR′═CR″—, wherein R′ and R″ aredefined as hereinbefore, but R′ and R″ preferably each are hydrogen.When the two carbon bridging species is ethylenic, that species can havean (E) or (Z) form, but most preferably is (E). In addition, m is aninteger and n is an integer such that the sum of m plus n is 0, 1, 2 or3, preferably is 0, 1 or 2, and more preferably is 0 or 1.

E, E′, E″ and E′″ individually represent hydrogen or a suitablenon-hydrogen substituent (e.g., alkyl, substituted alkyl,halo-substituted alkyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,alkylaryl, substituted alkylaryl, arylalkyl or substituted arylalkyl).E, E′, E″ and E′″ are preferably lower alkyl (e.g., straight chain orbranched alkyl including C₁-C₈, preferably C₁-C₅, such as methyl, ethyl,or isopropyl) or halo substituted lower alkyl (e.g., straight chain orbranched alkyl including C₁-C₈, preferably C₁-C₅, such astrifluoromethyl or trichloromethyl). Generally all of E, E′, E″ and E′″are hydrogen, or at least one E, E′, E″ and E″″ is non-hydrogen and theremaining E, E′, E″ and E′″ are hydrogen. For example, when m is 1 and nis 0, E and E′ each can be hydrogen, or E can be hydrogen and E′ can bemethyl; or when m is 1 and n is 1, E, E′, E″ and E′″ all can behydrogen, or E, E′ and E″ can be hydrogen and E′″ can be methyl, or E′,E″ and E′″ can be hydrogen and E can be methyl. Typically, the selectionof m, n, E, E′, E″ and E′″ is such that 0, 1 or 2, usually 0 or 1, andpreferably 0, of the substituents designated as E, E′, E″ and E′″ arenon-hydrogen (e.g., substituents such as alkyl or halo-substitutedalkyl). However, it is preferred that when m is 1 and n is 0, neither Enor E′ are substituted or unsubstituted aryl, heteroaryl, benzhydryl orbenzyl. Q is represented as follows:

where Z′″_(j) represents a suitable non-hydrogen substituent group(e.g., alkyl, substituted alkyl, halo-substituted alkyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl orsubstituted arylalkyl), but preferably alkyl. Z″ represents hydrogen orlower alkyl, and Z′ represents hydrogen, lower alkyl, acyl,alkoxycarbonyl or aryloxycarbonyl. Preferably, Z′ is hydrogen or methyland Z″ is hydrogen. In addition, j is an integer from 0 to 5, preferably0 or 1, most preferably 0; p is 0, 1 or 2, preferably 0 or 1, and mostpreferably 1; and q is 0, 1, 2 or 3, preferably 0 or 1, and mostpreferably 1. The dotted line indicates that the bond between the twoatoms can be either a single or a double bond.

As employed herein, “alkyl” refers to straight chain or branched alkylradicals including C₁-C₈, preferably C₁-C₅, such as methyl, ethyl, orisopropyl; “substituted alkyl” refers to alkyl radicals further bearingone or more substituent groups such as hydroxy, alkoxy, mercapto, aryl,heterocyclo, halo, amino, carboxyl, carbamyl, cyano, and the like;“alkenyl” refers to straight chain or branched hydrocarbon radicalsincluding C₁-C₈, preferably C₁-C₅ and having at least one carbon-carbondouble bond; “substituted alkenyl” refers to alkenyl radicals furtherbearing one or more substituent groups as defined above; “cycloalkyl”refers to saturated or unsaturated cyclic ring-containing radicalscontaining three to eight carbon atoms, preferably three to six carbonatoms; “substituted cycloalkyl” refers to cycloalkyl radicals furtherbearing one or more substituent groups as defined above; “aryl” refersto aromatic radicals having six to ten carbon atoms; “substituted aryl”refers to aryl radicals further bearing one or more substituent groupsas defined above; “alkylaryl” refers to alkyl-substituted aryl radicals;“substituted alkylaryl” refers to alkylaryl radicals further bearing oneor more substituent groups as defined above; “arylalkyl” refers toaryl-substituted alkyl radicals; “substituted arylalkyl” refers toarylalkyl radicals further bearing one or more substituent groups asdefined above; “heterocyclyl” refers to saturated or unsaturated cyclicradicals containing one or more heteroatoms (e.g., O, N, S) as part ofthe ring structure and having two to seven carbon atoms in the ring; and“substituted heterocyclyl” refers to heterocyclyl radicals furtherbearing one or more substituent groups as defined above.

Compounds of the present invention can occur as stereoisomericstructures, and the present invention relates to racemic mixtures ofsuch compounds as well as single enantiomer compounds.

Representative compounds useful in carrying out the present inventioninclude the following:

-   (S)-5-(pyrrolidin-2-ylethynyl)pyrimidine-   (R)-5-(pyrrolidin-2-ylethynyl)pyrimidine-   (S)-3-(pyrrolidin-2-ylethynyl)pyridine-   (R)-3-(pyrrolidin-2-ylethynyl)pyridine-   (S)-3-isopropoxy-5-(pyrrolidin-2-ylethynyl)pyridine-   (R)-3-isopropoxy-5-(pyrrolidin-2-ylethynyl)pyridine-   (S)-3-phenyl-5-(pyrrolidin-2-ylethynyl)pyridine-   (R)-3-phenyl-5-(pyrrolidin-2-ylethynyl)pyridine-   (S)-3-(4-methoxyphenoxy)-5-(pyrrolidin-2-ylethynyl)pyridine-   (R)-3-(4-methoxyphenoxy)-5-(pyrrolidin-2-ylethynyl)pyridine-   (S)-3-cyclopentyloxy-5-(pyrrolidin-2-ylethynyl)pyridine-   (R)-3-cyclopentyloxy-5-(pyrrolidin-2-ylethynyl)pyridine-   (S)-3-cyclohexyloxy-5-(pyrrolidin-2-ylethynyl)pyridine-   (RL)-3-cyclohexyloxy-5-(pyrrolidin-2-ylethynyl)pyridine-   (S)-3-(4-(pyrrolidine-1-sulfonyl)phenoxy)-5-(pyrrolidin-2-ylethynyl)pyridine-   (R)-3-(4-(pyrrolidine-1-sulfonyl)phenoxy)-5-(pyrrolidin-2-ylethynyl)pyridine-   (S)-3-(3-pyridyloxy)-5-(pyrrolidin-2-ylethynyl)pyridine-   (R)-3-(3-pyridyloxy)-5-(pyrrolidin-2-ylethynyl)pyridine-   (S)-3-(pyrrolidin-2-ylethynyl)-5-(tetrahydropyran-4-yloxy)pyridine-   (R)-3-(pyrrolidin-2-ylethynyl)-5-(tetrahydropyran-4-yloxy)pyridine-   (S)-3-(3,5-dihydroxy)phenoxy-5-(pyrrolidin-2-ylethynyl)pyridine-   (R)-3-(3,5-dihydroxy)phenoxy-5-(pyrrolidin-2-ylethynyl)pyridine-   (S)-N-[2-(5-pyrrolidin-2-ylethynylpyridin-3-yloxy)ethyl]benzamide-   (R)-N-[2-(5-pyrrolidin-2-ylethynylpyridin-3-yloxy)ethyl]benzamide-   (S)-3-(pyrrolidin-2-ylethynyl)-5-(3-methylsulfonylphenoxy)pyridine-   (R)-3-(pyrrolidin-2-ylethynyl)-5-(3-methylsulfonylphenoxy)pyridine-   (E,S)-3-(4-hydroxyphenoxy)-5-(pyrrolidin-2-ylvinyl)pyridine-   (E,R)-3-(4-hydroxyphenoxy)-5-(pyrrolidin-2-ylvinyl)pyridine-   (E,S)-3-cyclopentyloxy-5-(pyrrolidin-2-ylvinyl)pyridine-   (E,R)-3-cyclopentyloxy-5-(pyrrolidin-2-ylvinyl)pyridine-   (S)-3-isopropoxy-5-(pyrrolidin-2-ylvinyl)pyridine-   (R)-3-isopropoxy-5-(pyrrolidin-2-ylvinyl)pyridine-   (S)-3-phenyl-5-(pyrrolidin-2-ylvinyl)pyridine-   (R)-3-phenyl-5-(pyrrolidin-2-ylvinyl)pyridine-   (S)-3-(4-methoxyphenoxy)-5-(pyrrolidin-2-ylvinyl)pyridine-   (R)-3-(4-methoxyphenoxy)-5-(pyrrolidin-2-ylvinyl)pyridine-   (S)-3-cyclopentyloxy-5-(pyrrolidin-2-ylvinyl)pyridine-   (R)-3-cyclopentyloxy-5-(pyrrolidin-2-ylvinyl)pyridine-   (S)-3-cyclohexyloxy-5-(pyrrolidin-2-ylvinyl)pyridine-   (R)-3-cyclohexyloxy-5-(pyrrolidin-2-ylvinyl)pyridine-   (S)-3-(4-(pyrrolidine-1-sulfonyl)phenoxy)-5-(pyrrolidin-2-ylvinyl)pyridine-   (R)-3-(4-(pyrrolidine-1-sulfonyl)phenoxy)-5-(pyrrolidin-2-ylvinyl)pyridine-   (S)-3-(3-pyridyloxy)-5-(pyrrolidin-2-ylvinyl)pyridine-   (R)-3-(3-pyridyloxy)-5-(pyrrolidin-2-ylvinyl)pyridine-   (S)-3-(pyrrolidin-2-ylvinyl)-5-(tetrahydropyran-4-yloxy)pyridine-   (R)-3-(pyrrolidin-2-ylvinyl)-5-(tetrahydropyran-4-yloxy)pyridine-   (S)-3-(3,5-dihydroxy)phenoxy-5-(pyrrolidin-2-ylvinyl)pyridine-   (R)-3-(3,5-dihydroxy)phenoxy-5-(pyrrolidin-2-ylvinyl)pyridine-   (S)-N-[2-(5-pyrrolidin-2-ylvinylpyridin-3-yloxy)ethyl]benzamide-   (R)-N-[2-(5-pyrrolidin-2-ylvinylpyridin-3-yloxy)ethyl]benzamide-   (S)-3-(pyrrolidin-2-ylvinyl)-5-(3-methylsulfonylphenoxy)pyridine-   (R)-3-(pyrrolidin-2-ylvinyl)-5-(3-methylsulfonylphenoxy)pyridine-   5-(2-(5-azabicyclo[3.3.0]octyl)ethynyl)pyridine-   5-(2-(5-azabicyclo[3.3.0]octyl)ethynyl)-3-cyclopentyloxypyridine-   5-(2-(5-azabicyclo[3.3.0]octyl)ethynyl)pyrimidine-   (E)-5-(2-(3-pyridyl)vinyl)-1-azabicyclo[3.3.0]octane-   (Z)-5-(2-(3-pyridyl)vinyl)-1-azabicyclo[3.3.0]octane-   (E)-5-(2-(5-azabicyclo[3.3.0]octyl)vinyl)-3-cyclopentyloxypyridine-   (Z)-5-(2-(5-azabicyclo[3.3.0]octyl)vinyl)-3-cyclopentyloxypyridine-   (E)-5-(2-(5-azabicyclo[3.3.0]octyl)vinyl)pyrimidine-   (Z)-5-(2-(5-azabicyclo[3.3.0]octyl)vinyl)pyrimidine-   5-(2-(5-azabicyclo[3.3.0]octyl)ethyl)pyridine-   5-(2-(5-azabicyclo[3.3.0]octyl)ethyl)-3-cyclopentyloxypyridine-   5-(2-(5-azabicyclo[3.3.0]octyl)ethyl)pyrimidine

The manner in which certain compounds of the present invention aresynthesized can vary. Depending upon the enantiomeric purity of startingmaterials, compounds of the present invention can be prepared in eitherracemic form or in enantiomerically pure form. In one method, certainpyridyl olefinic pyrrolidine compounds can be prepared by using apalladium-catalyzed coupling reaction of a 3-bromopyridine or3-iodopyridine with an olefin possessing a protected pyrrolidinefunctionality, such as (2S)-2-allyl-N-(tert-butoxycarbonyl)pyrrolidine,also known as (2S)-N-(tert-butoxycarbonyl)-2-(3-prop-1-enyl)pyrrolidine.Reaction conditions employing palladium(II) acetate,tri-o-tolylphosphine and triethylamine (so-called Heck conditions),similar to those described by Frank et al., J. Org. Chem. 43 (15): 2947(1978) and Malek et al., J. Org. Chem. 47: 5395 (1982), can be used. Thetert-butoxycarbonyl protecting group of the resulting reaction product,(2S)-(2E)-N-(tert-butoxycarbonyl)-2-(3-prop-1-(3-pyridyl)-1-enyl)pyrrolidine,can then be removed by treatment with a strong acid, such astrifluoroacetic acid, to produce(2S)-(2E)-2-(3-prop-1-(3-pyridyl)-1-enyl)pyrrolidine. The pyrrolidinering can then be N-methylated using aqueous formaldehyde and sodiumcyanoborohydride using methodology similar to that described by Abreo etal., J. Med. Chem. 39: 817 (1996) to afford(2S)-(2E)-2-(3-(1-methylpyrrolidin-2-yl)prop-1-enyl)pyridine. Theaforementioned side chain,(2S)-2-allyl-N-(tert-butoxycarbonyl)pyrrolidine, can be prepared fromcommercially available (Aldrich Chemical Company)(2S)-2-pyrrolidinemethanol. The pyrrolidine nitrogen of the lattercompound can be protected by treatment with di-tert-butyl dicarbonate indichloromethane using triethylamine as a base to produce(2S)-N-(tert-butoxycarbonyl)-2-(hydroxymethyl)pyrrolidine. The lattercompound can be treated with iodine, triphenylphosphine, and diethylazodicarboxylate to give(2S)-N-(tert-butoxycarbonyl)-2-(iodomethyl)pyrrolidine. Treatment of thelatter compound with vinylmagnesium bromide and copper(I) iodideproduces the desired olefinic pyrrolidine,(2S)-2-allyl-N-(tert-butoxycarbonyl)pyrrolidine.

Since (2R)-2-pyrrolidinemethanol is also commercially available (AldrichChemical Company), the corresponding enantiomeric syntheticintermediates and compounds of the present invention, namely(2R)-2-allyl-N-(tert-butoxycarbonyl)pyrrolidine,(2R)-(2E)-N-(tert-butoxycarbonyl)-2-(3-prop-1-(3-pyridyl)-1-enyl)pyrrolidine,(2R)-(2E)-2-(3-prop-1-(3-pyridyl)-1-enyl)pyrrolidine and(2R)-(2E)-3-(3-(1-methylpyrrolidine-2-yl)prop-1-enyl)pyridine, can beprepared in a similar fashion. Alternatively, enantiomerically pure2-pyrrolidinemethanol can be synthetically elaborated to the desiredchiral olefinic pyrrolidine, 2-allyl-N-(tert-butoxycarbonyl)pyrrolidineusing the methodology of Ikeda et al., Heterocycles 50: 31 (1999).

The corresponding propargyl linked compounds can also be synthesizedfrom N-(tert-butoxycarbonyl)-2-(iodomethyl)pyrrolidine. Thus, treatmentwith lithium trimethylsilylacetylide, followed by deprotection usingtetrabutylammonium fluoride, will affordN-(tert-butoxycarbonyl)-2-(propargyl)pyrrolidine. This material can becoupled to 3-bromopyridine using so-called Sonogashira conditions,typically employing tetrakis(triphenylphosphine)palladium(0) andcopper(I) iodide as catalyst for the coupling. Procedures such as thosereported by Evans and Bach, Angew. Chem. Int. Ed. 32:1326 (1993) andYamanaka et al., Chem. Pharm. Bull. 29:3543 (1981) can be used. Theproduct,N-(tert-butoxycarbonyl)-2-(3-prop-1-(3-pyridyl)-1-ynyl)pyrrolidine, canbe deprotected by trifluoroacetic acid to give2-(3-prop-1-(3-pyridyl)-1-ynyl)pyrrolidine.

The manner in which certain 5-substituted-pyridyl olefinic pyrrolidinecompounds of the present invention are synthesized can vary. In onepreferred method, a 5-substituted-3-halo-pyridine compound is subjectedto a palladium-catalyzed reaction with an olefinic pyrrolidine compoundsuch as (2S)-2-allyl-N-(tert-butoxycarbonyl)pyrrolidine as describedabove. Removal of the tert-butoxycarbonyl protecting group affords(2S)-(2E)-2-(3-prop)-1-(5-substituted-3-pyridyl)-1-enyl)pyrrolidine,which can subsequently be N-methylated using aqueous formaldehyde andformic acid. In this manner, a number of 5-substituted pyridyl compoundsof the present invention can be prepared. In a similar fashion, if oneemploys a 5-halopyrimidine compound such as 5-bromopyrimidine in thisHeck reaction sequence, then the corresponding enantiomerically purepyrimidine compounds can be prepared, namely (2R)- and(2S)-(2E)-2-(3-prop-1-(5-pyrimidinyl)-1-enyl)pyrrolidine and (2R)- and(2S)-(2E)-5-(3-(1-methylpyrrolidin-2-yl)prop-1-enyl)pyrimidine.

In a similar manner, 2-allylquinuclidine can be subjected to apalladium-catalyzed coupling reaction with a 3-halopyridine, such as3-bromopyridine or 3-iodopyridine, to afford2-(1-(3-pyridyl)propen-3-yl)quinuclidine. The precursor,2-allylquinuclidine can be prepared from 3-quinuclidinone (commerciallyavailable from Aldrich Chemical Company) by alkylation and modifiedWolff-Kishner reduction. Thus, 3-quinuclidinone can be converted to thecorresponding imine with isopropylamine and molecular sieves. See, forexample, Forsyth et al., J. Am. Chem. Soc. 109:7270 (1987). Alkylationof the imine with lithium diisopropylamine and allyl bromide, followedby hydrolysis, produces 2-allyl-3-quinuclidinone. Removal of thecarbonyl-protecting group can then be effected by converting the ketoneinto the p-toluenesulfonylhydrazone followed by reduction with sodiumcyanoborohydride to afford 2-allylquinuclidine.

The manner in which certain pyridyl acetylenic pyrrolidine compounds ofthe present invention are synthesized can vary. In one method, apalladium-catalyzed reaction can be used for the coupling of a3-bromopyridine or a 3-iodopyridine with an alkyne possessing aprotected pyrrolidine functionality, such as(2S)-N-(tert-butoxycarbonyl)-2-propargylpyrrolidine. Reaction conditionsemploying tetrakis(triphenylphosphine)palladium(0), copper(I) iodide, abase such as triethylamine and an appropriate solvent, such as1,2-dimethoxyethane or N,N-dimethylformamide, can be used.Alternatively, the methodology set forth in Bleicher et al., Synlett.1115 (1995) can be used. The resulting coupling reaction product,(2S)-N-(tert-butoxycarbonyl)-2-(3-(3-pyridyl)prop-2-ynyl)pyrrolidine,can then be treated with a strong acid such as trifluoroacetic acid toremove the protecting group, producing(2S)-3-(3-pyrrolidin-2-ylprop-1-ynyl)pyridine. The latter compound canbe N-methylated by heating with formaldehyde and formic acid to afford(2S)-3-(3-(1-methylpyrrolidin-2-yl)prop-1-ynyl)pyridine. Theaforementioned alkyne,(2S)-N-(tert-butoxycarbonyl)-2-propargylpyrrolidine can be prepared bytreatment of (2S)-N-(tert-butoxycarbonyl)-2-(iodomethyl)pyrrolidine (thesynthesis of which has been previously described above) with the lithiumsalt of trimethylsilylacetylene or with lithium acetylide,ethylenediamine complex (commercially available from Aldrich ChemicalCompany) followed by desilylation, if necessary, using potassiumfluoride in acetonitrile. The corresponding enantiomers,(2R)-3-(3-pyrrolidin-2-ylprop-1-ynyl)pyridine and(2R)-3-(3-(1-methylpyrrolidin-2-yl)prop-1-ynyl)pyridine can besynthesized from the enantiomeric alkyne,(2R)-N-(tert-butoxycarbonyl)-2-propargylpyrrolidine, which ultimatelycan be prepared from (2R)-2-pyrrolidinemethanol (available from AldrichChemical Company).

In addition, the shorter chain length analogs are readily prepared from(2S)-N-(tert-butoxycarbonyl)-2-(hydroxymethyl)pyrrolidine. A Swernoxidation using oxalyl chloride to produce the aldehyde (Swern et al.,J. Org. Chem. 41:3329 (1976)) followed by conversion to the olefin,using the techniques described in Wittig et al., Liebigs Ann. 562:187(1949), provides (2S)-N-(tert-butoxycarbonyl)-2-vinylpyrrolidine. Thecorresponding alkyne,(2S)-N-(tert-butoxycarbonyl)-2-(ethynyl)pyrrolidine, may be prepared bytreatment of the aldehyde with carbon tetrabromide andtriphenylphosphine followed by n-butyl lithium.

Compounds of the present invention possessing a shorter olefinic sidechain can be prepared by a variety of methods. In one approach usingsimilar palladium-catalyzed coupling methods, a 3-halopyridine, such as3-bromopyridine or 3-iodopyridine, is coupled with(2S)-N-(tert-butoxycarbonyl)-2-vinylpyrrolidine. The latter olefinicpyrrolidine compound can be prepared according to the techniquesdescribed by Ikeda et al., supra, starting from commercially available(2S)-2-pyrrolidinemethanol. The protecting group can then be removedfrom the resulting reaction product,(2S)-(2E)-N-(tert-butoxycarbonyl)-3-(2-pyrrolidin-2ylvinyl)pyridine,using trifluoroacetic acid to give(2S)-(2E)-3-(2-pyrrolidin-2-ylvinyl)pyridine. The latter compound can beN-methylated using the previously described methodology. By using(2R)-2-pyrrolidinemethanol, the corresponding enantiomers of the abovecompounds can be prepared.

Certain compounds of the present invention possessing a shorteracetylenic side chain can be prepared by a variety of methods. In onesynthetic approach, a 3-halopyridine such as 3-bromopyridine can becoupled with an alkyne possessing a protected pyrrolidine functionalitysuch as (2S)-N-(tert-butoxycarbonyl)-2-ethynylpyrrolidine. Reactionconditions employing a palladium catalyst such astetrakis(triphenylphosphine)palladium(0), copper(I) iodide,triethylamine and a solvent such as N,N-dimethylformamide can be used.The resulting reaction product,(2S)-N-(tert-butoxycarbonyl)-3-(2-pyrrolidin-2-ylethynyl)pyridine, canbe treated with a strong acid such as trifluoroacetic acid to afford(2S)-3-(2-pyrrolidin-2-ylethynyl)pyridine. Treatment of the lattercompound with formic acid and formaldehyde or formaldehyde and sodiumcyanoborohydride affords the N-methyl analog,(2S)-3-(2-(1-methylpyrrolidin-2-yl)ethynyl)pyridine. The aforementionedalkyne, (2S)-N-(tert-butoxycarbonyl)-2-ethynylpyrrolidine, can beprepared from N-(tert-butoxycarbonyl)-(S)-proline according to themethods described in WO 97/05139 to Elliot et al. By using theenantiomeric alkyne, (2R)-N-(tert-butoxycarbonyl)-2-ethynylpyrrolidine,prepared from N-(tert-butoxycarbonyl)-(R)-proline, the enantiomers ofthe above compounds of the present invention can be prepared.

There are a number of methods by which the (Z)-olefinic isomers ofpyridyl olefinic pyrrolidine compounds can be synthetically produced. Inone approach, these (Z)-olefinic isomers can be prepared by thecontrolled hydrogenation of the corresponding alkynyl compounds (e.g., a3-(3-pyrrolidin-2-ylprop-1-ynyl)pyridine-type compound) usingcommercially available Lindlar catalyst (Aldrich Chemical Company) usingthe methodology set forth in Lindlar et al., Org. Syn. 46: 89 (1966).

A great variety of 5-substituted-3-bromopyridines can be used in eitherSonogashira (with alkynes) or Heck (with alkenes) coupling reactions, asdescribed previously. These 5-substituted-3-bromopyridines can bereadily made from commercially available 3,5-dibromopyridine. Thus,Suzuki coupling of 3,5-dibromopyridine with arylboronic acids, in thepresence of a palladium catalyst, gives 5-aryl-3-bromopyridines.Procedures such as those described by Guillier, et al., J. Org. Chem.60: 292 (1995) can be used. This methodology has been used synthesize5-phenyl and 5-(4-phenoxyphenyl) analogs. In another example,3-bromo-5-isopropoxypyridine is readily prepared from3,5-dibromopyridine and sodium isopropoxide. This methodology isextremely general and has been utilized to prepare a variety of5-alkoxy- and 5-aryloxy-substituted analogs including 5-phenoxy-,5-cyclopentyloxy-, 5-cyclohexyloxy-, 5-(4-methoxyphenoxy)-,5-(3,5-dimethoxyphenoxy)- and 3-pyridyloxy-substituted analogs. In eachcase, the 5-alkoxy- or 5-aryloxy-3-bromopyridine is made by reaction of3,5-dibromopyridine with the corresponding sodium alkoxide or sodiumaryloxide. The simple 5-alkoxy-3-bromopyridines (methoxy, ethoxy,isopropoxy) can be readily hydrolyzed, by the action of hydrobromicacid, to 5-hydroxy-3-bromopyridine. This intermediate can also becoupled to both alkenes and alkynes in palladium-catalyzed processes,providing 5-hydroxy analogs. Alkylthiolates and arylthiolates will alsoreact with 3,5-dibromopyridine to give 5-alkylthio- and5-arlythio-3-bromopyridines. These sulfur containing species can be usedin palladium-catalyzed coupling reactions as well.

The 5-hydroxy-3-bromopyridine intermediate is also versatile, being asubstrate for several different alkylation/arylation reactions. Thus, itcan be employed in nucleophilic aromatic substitution reactions withelectron-deficient aromatic rings. For instance, reaction with1-((4-fluoropheny)sulfonyl)pyrrolidine, in the presence of carbonatebase, gives 3-bromo-5-(4-(pyrrolidine-1-sulfonyl)phenoxy)pyridine. Otheraromatic halides can be employed as electrophiles (e.g.,4-fluorobenzonitrile and 4-chloropyrimidine).

The Mitsunobu reaction of 5-hydroxy-3-bromopyridine with variousalcohols provides a route to complex alkoxy substituents. Thus,3-bromo-5-(tetrahydropyran-4-yloxy)pyridine can be made by reaction of5-hydroxy-3-bromopyridine with tetrahydropyran-4-ol, usingtriphenylphosphine and diethyl azodicarboxylate, as described inMitsunobu et al., Bull. Chem. Soc. Jpn. 40:2380 (1967) and Mitsunobu,Synthesis 1 (1981). Other complex alcohol substrates can be employed inthis reaction (e.g., N-phenyl-4-piperidinol and(2S)-N-trifluoroacetyl-2-pyrrolidinemethanol).

Williamson ether synthesis can also be used to generate complex alkoxyanalogs. Thus, reaction of 5-hydroxy-3-bromopyridine withN-(2-chloroethyl)phthalimide gives3-bromo-5-(2-phthalimidoethoxy)pyridine. Subsequently, the phthaloylprotecting group can be removed and a variety of amides produced fromthe resulting amine.

The manner in which compounds of the present invention can besynthesized can vary. In another approach, 5-bromonicotinic acid is asuitable precursor of various 5-substituted-3-bromopyridines. Thecarboxylic acid functionality can be converted into a variety ofderivative functionalities, using methods familiar to those skilled inthe art of organic synthesis. Thus, the corresponding esters and amides(both unsubstituted and substituted) are readily prepared from the acid.These can be used directly in palladium-catalyzed coupling reactions orfurther transformed to other derivatives. For instance, certain amidesare known to readily undergo nucleophilic acyl substitution to produceketones. Thus, the so-called Weinreb amides (N-methoxy-N-methylamides)react with aryllithium reagents to produce the corresponding diarylketones. For example, see Selnick, et al., Tetrahedron Lett. 34: 2043(1993). In this manner 5-(arylcarbonyl)-3-bromopyridines can be made.Such compounds can also be synthesized by conversion of 5-bromonicotinicacid to the acyl chloride (using thionyl chloride), followed byFriedel-Crafts-type acylation. See, for example, Villani and King, Org.Syn. Coll. Vol. 4: 88 (1963). The 5-(arylcarbonyl)-3-bromo-pyridines, inturn, serve as substrates for the palladium-catalyzed couplingreactions, leading to compounds of the present invention.

5-Bromonicotinamide, produced from acid chloride by reaction withammonia, can be converted by the action of sodium hypochloride into3-amino-5-bromopyridine. This material can be coupled, in apalladium-catalyzed process, to the N-(tert-butoxycarbonyl)azacyclicalkenes and alkynes previously described to give compounds of thepresent invention. The resulting 5-amino substituted compounds can befurther transformed, by diazonium ion chemistry, to give various5-substituted analogs. Among the other 5-substituted analogs that can beproduced from 5-diazonium salt intermediates are: 5-hydroxy analogs,5-alkoxy analogs, 5-fluoro analogs, 5-chloro analogs, 5-bromo analogs,5-iodo analogs, 5-cyano analogs and 5-mercapto analogs. These compoundscan be synthesized using the general techniques set forth in Zwart etal., Recueil Trav. Chim. Pays-Bas 74:1062 (1955). For example, 5-hydroxysubstituted analogs can be prepared from the reaction of thecorresponding 5-diazonium salt intermediates with water. 5-Alkoxyanalogs can be made from the reaction of the diazonium salts withalcohols. 5-Fluoro substituted analogs can be prepared from the reactionof the 5-diazonium salt intermediates with fluoroboric acid. 5-Chlorosubstituted analogs can be prepared from the reaction of the 5-aminocompounds with sodium nitrite and hydrochloric acid in the presence ofcopper chloride. 5-Cyano substituted analogs can be prepared from thereaction of the corresponding 5-diazonium salt intermediates withpotassium copper cyanide. Appropriate 5-diazonium salt intermediates canalso be used for the synthesis of mercapto-substituted analogs using thegeneral techniques described in Hoffman et al., J. Med. Chem. 36: 953(1993). The 5-mercapto-substituted analogs can in turn be converted tothe 5-alkylthio-substituted analogs by reaction with sodium hydride andan appropriate alkyl bromide. 5-Acylamido analogs of the aforementionedcompounds can be prepared by reaction of the corresponding 5-aminocompounds with an appropriate acid anhydride or acid chloride usingtechniques known to those skilled in the art of organic synthesis.

5-Hydroxy-substituted analogs of the aforementioned compounds can beused to prepare corresponding 5-alkanoyloxy-substituted compounds byreaction with the appropriate acid, acid chloride, or acid anhydride.5-Cyano-substituted analogs of the aforementioned compounds can behydrolyzed to afford the corresponding 5-carboxamido-substitutedcompounds. Further hydrolysis results in formation of the corresponding5-carboxylic acid-substituted analogs. Reduction of the5-cyano-substituted analogs with lithium aluminum hydride yields thecorresponding 5-aminomethyl analogs. 5-Acyl-substituted analogs can beprepared from corresponding 5-carboxylic acid-substituted analogs byreaction with an appropriate alkyl lithium using techniques known tothose skilled in the art.

5-Carboxylic acid-substituted analogs of the aforementioned compoundscan be converted to the corresponding esters by reaction with anappropriate alcohol and acid catalyst. Compounds with an ester group atthe 5-pyridyl position can be reduced with sodium borohydride or lithiumaluminum hydride to produce the corresponding5-hydroxymethyl-substituted analogs. These analogs in turn can beconverted to compounds bearing an ether moiety at the 5-pyridyl positionby reaction with sodium hydride and an appropriate alkyl halide, usingconventional techniques. Alternatively, the 5-hydroxymethyl-substitutedanalogs can be reacted with tosyl chloride to provide the corresponding5-tosyloxymethyl analogs. The 5-carboxylic acid-substituted analogs canalso be converted to the corresponding 5-alkylaminoacyl analogs byreaction with an appropriate alkylamine and thionyl chloride.

5-Tosyloxymethyl-substituted analogs of the aforementioned compounds canbe converted to the corresponding 5-methyl-substituted compounds byreduction with lithium aluminum hydride. 5-Tosyloxymethyl-substitutedanalogs of the aforementioned compounds can also be used to produce5-alkyl-substituted compounds via reaction with an alkyllithium.5-Hydroxy-substituted analogs of the aforementioned compounds can beused to prepare 5-N-alkylcaroamoyloxy-substituted compounds by reactionwith N-alkylisocyanates. 5-Amino-substituted analogs of theaforementioned compounds can be used to prepare5-N-alkoxycarboxamido-substituted compounds by reaction with alkylchloroformate esters, using techniques known to those skilled in the artof organic synthesis.

The manner in which certain compounds of the present invention areprepared can vary. For example, compounds that possess certainfused-ring heterocycles can be prepared by the Heck or Sonogashirareactions. Such compounds can be synthesized by the palladium-catalyzedcoupling of a bromo-heterocyclic compound, such as6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine, with the previouslymentioned N-(tert-butoxycarbonyl)-protected olefinic or acetylenicamines, such (2S)-2-vinyl-N-(tert-butoxycarbonyl)pyrrolidine or(2S)-2-ethynyl-N-(tert-butoxycarbonyl)pyrrolidine. Typically, the typesof procedures set forth in Frank et al., J. Org. Chem. 43: 2947 (1978)and Malek et al., J. Org. Chem. 47: 5395 (1982) involving apalladium-catalyzed coupling of an olefin and an aromatic halide areused for the coupling reaction. Procedures such as those reported byEvans and Bach, Angew. Chem. Int. Ed. 32:1326 (1993) and Yamanaka etal., Chem. Pharm. Bull. 29:3543 (1981) for the coupling of alkynes toaromatic halides can be used. The resulting tert-butoxycarbonylprotected intermediate can be deprotected by treatment with a strongacid, such as trifluoroacetic acid. The aforementionedbromo-imidazopyridine, 6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine can beprepared yield by heating 2,3-diamino-5-bromopyridine with acetic acidin polyphosphoric acid according to the methods described by Dubey etal., Indian J. Chem. 16B(6):531 (1978). 2,3-Diamino-5-bromopyridine canbe prepared yield by heating 2-amino-5-bromo-3-nitropyridine(commercially available from Aldrich Chemical Company and LancasterSynthesis, Inc) with tin(II) chloride dihydrate in boiling ethanolaccording to the techniques described by Cai et al., J. Med. Chem.40(22): 3679 (1997).

In another example, a bromo fused-ring heterocycle, such as6-bromo-1,3-dioxolo[4,5-b]pyridine, can be coupled with the previouslymentioned N-(tert-butoxycarbonyl) protected olefinic or acetylenicazacyclic compounds using the Heck or Sonogashira reactions. Theresulting intermediate can be deprotected with a strong acid such astrifluoroacetic acid. The aforementioned bromo compound,6-bromo-1,3-dioxolo[4,5-b]pyridine, can be synthesized from5-bromo-2,3-dihydroxypyridine, also known as 5-bromo-3-hydroxy-2(1H)-pyridinone, via a methylenation procedure using bromochloromethanein the presence of potassium carbonate and N,N-dimethylformamideaccording to the methodology of Dallacker et al., Z. Naturforsch. 34b:1729 (1979). 5-Bromo-2,3-dihydroxypyridine can be prepared fromfurfural (2-furaldehyde, commercially available from Aldrich ChemicalCompany and Lancaster Synthesis, Inc) using the methods described inDallacker et al., supra. Alternatively, 5-bromo-2,3-dihydroxypyridinecan be prepared according to the techniques described in EP 0081745 toRose and Maak.

In another example of a compound that possesses a fused-ringheterocycle, the bromo compound7-bromo-2,3-dihydro-1,4-dioxino[2,3-b]pyridine (also known as7-bromo-5-aza-4-oxachromane) can be condensed with the previouslymentioned azacyclic alkenes and alkynes. The resulting compound can bedeprotected with a strong acid such as trifluoroacetic acid.7-Bromo-2,3-dihydro-1,4-dioxino[2,3-b]pyridine can be prepared bytreating 5-bromo-2,3-dihydroxypyridine with 1,2-dibromoethane andpotassium carbonate in N,N-dimethylformamide according to themethodology of Dallacker et al., supra. 5-Bromo-2,3-dihydroxypyridinecan be prepared from furfural as described above.

Other polycyclic aromatic compounds of the present invention can beprepared by the Heck or Sonogashira reactions. Thus, certain compoundscan be synthesized by the palladium-catalyzed coupling of a bromofused-ring heterocycle, such as6-bromo-1H-imidazo[4,5-b]pyridine-2-thiol, with the previously mentionedolefinic and acetylenic azacycles. The intermediate resulting from thecoupling reaction can be subjected to treatment with a strong acid, suchas trifluoroacetic acid, so remove the protecting group. Theaforementioned bromo compound,6-bromo-1H-imidazo[4,5-b]pyridine-2-thiol, can be prepared by treating6-bromo-1H-imidazo[4,5-b]pyridine with sulfur at 230-260° C. accordingto the methods described in Yutilov, Khim. Geterotsikl Doedin. 6: 799(1988). 6-Bromo-1H-imidazo[4,5-b]pyridine can be obtained fromSigma-Aldrich Chemical Company. Alternatively,6-bromo-1H-imidazo[4,5-b]pyridine can be prepared by treating2,3-diamino-5-bromopyridine with formic acid in polyphosphoric acidusing methodology similar to that described by Dubey et al., supra.2,3-Diamino-5-bromopyridine can be prepared by heating2-amino-5-bromo-3-nitropyridine (commercially available from AldrichChemical Company and Lancaster Synthesis, Inc) with tin(II) chloridedihydrate in boiling ethanol according to the techniques described byCai et al., supra. Alternatively,6-bromo-1H-imidazo[4,5-b]pyridine-2-thiol can be prepared by h eating2,3-diamino-5-bromopyridine with K⁺⁻-SCSOEt in aqueous ethanol usingmethodology similar to that described by Kuhler et al., J. Med. Chem.38(25): 4906 (1995). 2,3-Diamino-5-bromopyridine can be prepared from2-amino-5-bromo-3-nitropyridine as described above.

In a related example,6-bromo-2-phenylmethylthio-1H-imidazo[4,5-b]pyridine can be coupled viaHeck or Sonogashira reactions with the previously mentioned olefinic andacetylenic azacycles. The resulting intermediate can be subjected totreatment with a strong acid, such as trifluoroacetic acid, to removethe protecting group.6-Bromo-2-phenylmethylthio-1H-imidazo[4,5-b]pyridine can be prepared byalkylating the previously described6-bromo-1H-imidazo[4,5-b]pyridine-2-thiol with benzyl bromide in thepresence of potassium carbonate and N,N-dimethylformamide.

In another example, 6-bromooxazolo[4,5-b]pyridine can be subjected topalladium-catalyzed coupling and deprotection of the resultingintermediate with trifluoroacetic acid. 6-Bromooxazolo[4,5-b]pyridinecan be produced from 2-amino-5-bromo-3-pyridinol by condensation withformic acid or a trialkyl orthoformate, using methodology similar tothat of Viaud et al., Heterocycles 41: 2799 (1995). The use of othercarboxylic acids produces 2-substituted-6-bromooxazolo[4,5-b]pyridines,which are also substrates for the Heck and Sonogashira reactions. Thesynthesis of 2-amino-5-bromo-3-pyridinol proceeds from furfurylamine(Aldrich Chemical Company). Thus, 5-bromo-3-pyridinol (produced fromfurfurylamine according to U.S. Pat. No. 4,192,946) can be chlorinated,using methods described by Koch et al., Synthesis, 499 (1990), to give2-chloro-5-bromo-3-pyridinol, which in turn can be converted to2-amino-5-bromo-3-pyridinol by treatment with ammonia.

5-Bromooxazolo[5,4-b]pyridine, isomeric by orientation of ring fusion tothe previously described 6-bromooxazolo[4,5-b]pyridine, can also be usedin the Heck and Sonogashira coupling and subsequent deprotection.5-Bromooxazolo[5,4-b]pyridine is synthesized from3-amino-5-bromo-2-pyridinol (3-amino-5-bromo-2-pyridone) by thecondensation with formic acid (or a derivative thereof) as describedabove. 3-Amino-5-bromo-2-pyridinol can be made by bromination (usingtechniques described by Batkowski, Rocz. Chem. 41: 729 (1967)) andsubsequent tin(II) chloride reduction (according to the method describedby Cai et al., supra) of commercially available 3-nitro-2-pyridinol(Aldrich Chemical Company).

Other polycyclic aromatic compounds of the present invention can beprepared by the Heck and Sonogashira reactions. Thus, both5-bromofuro[2,3-b]pyridine and 5-bromo-1H-pyrrolo[2,3-b]pyridine canundergo palladium-catalyzed coupling with the previously describedolefinic and acetylenic azacycles. Subsequent removal of thetert-butoxycarbonyl group can be achieved with trifluoroacetic acid. Theaforementioned 5-bromofuro[2,3-b]pyridine and5-bromo-1H-pyrrolo[2,3-b]pyridine can be made from2,3-dihydrofuro[2,3-b]pyridine and 2,3-dihydropyrrolo[2,3-b]pyridinerespectively, by bromination (bromine and sodium bicarbonate inmethanol) and dehydrogenation(2,3-dichloro-5,6-dicyano-1,4-benzoquinone), using chemistry describedby Taylor et al., Tetrahedron 43: 5145 (1987).2,3-Dihydrofuro[2,3-b]pyridine and 2,3-dihydropyrrolo[2,3-b]pyridineare, in turn, made from 2-chloropyrimidine (Aldrich Chemical Company) bynucleophilic displacement of the chloride (with the sodium salt of3-butyn-1-ol or with 4-amino-1-butyne) and subsequent intramolecularDiels-Alder reaction, as described by Frissen et al., Tetrahedron 45:803 (1989). Using similar chemistry, 2,3-dihydrofuro[2,3-b]pyridine and2,3-dihydropyrrolo[2,3-b]pyridine are also produced from3-methylthio-1,2,4-triazene (Taylor et al., supra), which in turn ismade from glyoxal and S-methylthiosemicarbazide as described by Paudleret al., J Heterocyclic Chem. 7: 767 (1970).

Brominated dihydrofuropyridines, dihydropyrrolopyridines, anddihydropyranopyridines are also substrates for the palladium-catalyzedcoupling. For instance, both 5-bromo-2,3-dihydrofuro[2,3-b]pyridine and5-bromo-2,3-dihydropyrrolo[2,3-b]pyridine (from bromination of2,3-dihydrofuro[2,3-b]pyridine and 2,3-dihydropyrrolo[2,3-b]pyridine, asdescribed above) can be coupled with the previously mentioned olefinicor acetylenic azacyamine side chain in a Heck process and subsequentdeprotection. Similarly, 6-bromo-2,3-dihydrofuro[3,2-b]pyridine(isomeric at the ring fusion with the [2,3-b]system) can also be used ina Heck process. The aforementioned6-bromo-2,3-dihydrofuro[3,2-b]pyridine can be made from5-bromo-2-methyl-3-pyridinol by sequential treatment with twoequivalents of lithium diisopropylamide (to generate the 2-methylenyl,3-oxy dianion) and one equivalent of dibromomethane. Alternatively,using chemistry similar to that described by Koller et al., Synth.Commun. 25: 2963 (1995), the silyl-protected pyridinol(5-bromo-2-methyl-3-trimethylsilyloxypyridine) can be treatedsequentially with one equivalent of lithium diisopropylamide and analkyl or aryl aldehyde to produce a 2-(2-(1-alkyl- or1-aryl-1-hydroxy)ethyl)-5-bromo-3-(trimethylsilyloxy)pyridine. Suchmaterials can be converted, by methods (such as acid catalyzedcyclization or the Williamson synthesis) known to those skilled in theart, into the corresponding cyclic ethers 2-alkyl- or2-aryl-6-bromo-2,3-dihydrofuro[3,2-b]pyridines. Similar chemistry, inwhich epoxides (instead of aldehydes) are used in reaction with thepyridylmethyl carbanion, leads to 2-alkyl- and2-aryl-7-bromo-2,3-dihydropyrano[3,2-b]pyridines. These 2-substituted,brominated dihydrofuro- and dihydropyranopyridines are also substratesfor the Heck reaction. For instance,6-bromo-2,3-dihydro-2-phenylfuro[3,2-b]pyridine can be coupled in apalladium-catalyzed process and the coupling product treated withtrifluoroacetic acid to deprotect.

The 5-bromo-2-methyl-3-pyridinol, required for the syntheses of thebrominated dihydrofuro- and dihydropyranopyridines, is produced bystandard transformations of commercially available materials. Thus,2-methylnicotinic acid (Aldrich Chemical Company) can be converted bysequential treatment with thionyl chloride, bromine, and ammonia, asdescribed by Greco et al., J Het. Chem. 7: 761 (1970), into5-bromo-2-methylnicotinamide. Hofmann rearrangement of5-bromo-2-methylnicotinamide with hypochlorite will give3-amino-5-bromo-2-methylpyridine, which can be converted to5-bromo-2-methyl-3-pyridinol by diazotization with sodium nitrite inaqueous sulfuric acid. Alternatively, alanine ethyl ester (AldrichChemical Company) is converted (using ethyl formate) into its N-formylderivative, which is then converted to 5-ethoxy-4-methyloxazole usingphosphorous pentoxide (see Takeo et al., Japan Patent No. 45,012,732). ADiels-Alder reaction of 5-ethoxy-4-methyloxazole with acrylonitrilegives 5-hydroxy-6-methylnicotinonitrile, as described by Yoshikawa etal., Chem. Pharm. Bull. 13: 873 (1965), which is converted to5-amino-2-methyl-3-pyridinol by hydration (nitrile

amide) and Hoffman rearrangement (see Morisawa et al., Agr. Biol. Chem.39: 1275 (1975)). The 5-amino-2-methyl-3-pyridinol can then beconverted, by diazotization in the presence of copper (I) bromide, tothe desired 5-bromo-2-methyl-3-pyridinol.

The manner in which certain aryl substituted olefinic amine compoundspossessing an azetidinyl moiety are synthesized can vary. Using onesynthetic approach, 3-(2-(2-azetidinyl)vinyl)pyridine can be synthesizedstarting from commercially azetidine-4-carboxylic acid (Aldrich ChemicalCompany). Azetidine-2-carboxylic acid can be reduced by any of a numberof methods common to the art, such as treatment with lithium aluminumhydride to give azetidine-2-methanol. Protection of the azetidinylnitrogen of the latter compound can be accomplished by treatment withtert-butylpyrocarbonate and base to giveN-(tert-butoxycarbonyl)azetidine-2-methanol, using methodology similarto that described by Carpino et al., Acc. Chem. Res. 6:191 (1973). Thisalcohol can be converted to the alkyl iodide using diethylazodicarboxylate, triphenylphosphine and iodine according to theprocedure of Mitsunobu described previously. Treatment ofN-(tert-butoxycarbonyl)-2-(iodomethyl)azetidine with magnesium underanhydrous conditions followed by pyridine-3-carboxaldehyde affords theGrignard product,N-(tert-butoxycarbonyl)-2-(2-azetidinyl)-1-(3-pyridyl)ethan-1-ol.Treatment of the latter compound with methanesulfonyl chloride gives theO-mesylate, which can in turn be eliminated to giveN-(tert-butoxycarbonyl)-3-(2-(2-azetidinyl)vinyl)pyridine using1,8-diazabicyclo[5.4.0]undec-7-ene, in accordance with the methoddescribed by Wolkoff, J. Org. Chem. 47:1944 (1982). Finally, theprotecting group can be removed under acidic conditions, such astreatment with trifluoroacetic acid, to give the desired product3-(2-(2-azetidinyl)vinyl)pyridine.

The manner in which certain aryl-substituted olefinic amine compoundspossessing an azabicyclo[2.2.1]heptane functionality are synthesized canvary. 2-(2-(3-Pyridyl)vinyl-7-azabicyclo[2.2.1]heptane can besynthesized starting with ethyl7-aza-7-(ethoxycarbonyl)bicyclo[2.2.1]heptane-2-carboxylate which can begenerated from commercially available tropinone (Lancaster ChemicalCompany) according to the method of Badio et al., Eur. J. Pharmacol.321:865 (1997). This compound can then be reduced to ethyl7-aza-2-(hydroxymethyl)bicyclo[2.2.1]heptane-7-carboxylate using excessdiisobutylaluminum hydride. The resulting alcohol can then be convertedto ethyl 7-aza-2-(iodomethyl)bicyclo[2.2.1]heptane-7-carboxylate usingdiethyl azodicarboxylate, triphenylphosphine and iodine in a Mitsunobureaction. Conversion of ethyl7-aza-2-(iodomethyl)bicyclo[2.2.1]heptane-7-carboxylate to the magnesiumGrignard reagent, followed by reaction with pyridine 3-carboxaldehydeaffords the alcohol, ethyl2-(2-(3-pyridyl)-2-hydroxyethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate.Treatment of the latter compound with methanesulfonyl chloride yieldsthe O-mesylate, which can in turn be eliminated to give ethyl2-(2-(3-pyridyl)vinyl-7-azabicyclo[2.2.1]heptane-7-carboxylate using1,8-diazabicyclo[5.4.0]undec-7-ene in accordance with the methoddescribed by Wolkoff, supra. The desired product,2-(2-(3-pyridyl)vinyl-7-azabicyclo[2.2.1]heptane, can be obtained bytreatment of the latter compound with refluxing aqueous hydrochloricacid.

The manner in which certain aryl-substituted olefinic amine compoundspossessing a 2-azabicyclo[2.2.1]heptane moiety are synthesized can vary.In one synthetic approach, ethyl3-aza-3-((4-toluenesulfonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylate,synthesized according to the method of Hamley et al., Synlett. 29(1991), can be reduced to2-aza-3-(hydroxymethyl)-2-((4-toluenesulfonyl)bicyclo[2.2.1]hept-5-eneusing an excess of diisobutyllithium hydride at 0° C. Reduction of theolefin can be accomplished by various methods known to those skilled inthe art, such as hydrogenation over a palladium catalyst, to give2-aza-3-(hydroxymethyl)-2-((4-toluenesulfonyl)bicyclo[2.2.1]heptane.This alcohol can then be converted to2-aza-3-(iodomethyl)-2-((4-toluenesulfonyl)bicyclo[2.2.1]heptane usingdiethyl azodicarboxylate, triphenylphosphine and iodine as describedpreviously. Conversion of the latter alkyl iodide to the Grignardreagent, followed by reaction with pyridine 3-carboxaldehyde, affords3-(2-(3-pyridyl)-2-hydroxyethyl)-2-aza-2-((4-toluenesulfonyl)bicyclo[2.2.1]heptane.Treatment of the latter compound with methanesulfonyl chloride yieldsthe O-mesylate, which can in turn be eliminated to give3-(2-(3-pyridyl)vinyl)-2-aza-2-((4-toluenesulfonyl)bicyclo[2.2.1]heptaneusing 1,8-diazabicyclo[5.4.0]undec-7-ene in accordance with the methodsdescribed above. Finally, the desired product,3-(2-(3-pyridyl)vinyl)-2-azabicyclo[2.2.1]heptane, can be obtained bytreatment of the aforementioned N-tosylate with sodium naphthylideaccording to the procedure of Ji et al., J. Am. Chem. Soc. 89:5311(1967).

The manner in which certain aryl ethynyl azabicyclic compoundspossessing a 1-azabicyclo[3.3.0]octane moiety are synthesized can vary.In one approach, compounds such as5-(2-(5-azabicyclo[3.3.0]octyl)ethynyl)pyridine can be prepared by theaddition of the lithium salt of 3-ethynylpyridine to1,2,3,5,6,7-hexahydropyrrolizinium perchlorate at low temperature (−78°C.). The required starting material, 3-ethynylpyridine can be preparedfrom pyridine-3-carboxaldehyde by treatment with tetrabromomethane andtriphenylphosphine, followed by treatment of the resulting1,1-dibromo-2-(3-pyridyl)ethylene with n-butyllithium at low temperature(−78° C.) according to synthetic methods set forth in U.S. Pat. No.5,616,707 to Crooks et al. Alternatively, 3-ethynylpyridine can beprepare by the copper (I) iodide and palladium-catalyzed alkynylation of3-bromopyridine with 2-methyl-3-butyn-2-ol, followed by heating theresulting intermediate with a strong base such as sodium hydride,according to synthetic methods similar to those described by Cosford etal., J Med. Chem. 39: 3235 (1996), and Bleicher et al., J. Org. Chem.,63: 1109 (1998). The aforementioned 1,2,3,5,6,7-hexahydropyrroliziniumperchlorate can be prepared according to the general synthetic methodsof Miyano et al., Synthesis, 701 (1978) and Miyano et al, J Het. Chem.19:1465 (1982).

In another synthetic approach, compounds such as5-(2-(5-azabicyclo[3.3.0]octyl)ethynyl)pyridine can be prepared by thepalladium-catalyzed Sonagashira coupling (Thorand et al, J. Org. Chem.63: 8551 (1998)) of 3-bromopyridine and1-aza-5-ethynylbicyclo[3.3.0]octane. Catalysts, such as copper (I)iodide and bis(triphenylphosphine)palladium dichloride, andtriethylamine as a base in dichloromethane as a solvent can be used. Therequired synthetic intermediate, 1-aza-5-ethynylbicyclo[3.3.0]octane canbe prepared by the addition of 1,2,3,5,6,7-hexahydropyrroliziniumperchlorate to a solution of ethynylmagnesium bromide in tetrahydrofuranaccording to synthetic methods set forth in U.S. Pat. No. 5,733,912 toWasicak et al.

The manner in which certain aryl vinyl azabicyclic compounds of thepresent invention are synthesized can vary. In one approach, compoundssuch as (E)-5-(2-(3-pyridyl)vinyl)-1-azabicyclo[3.3.0]octane can besynthesized by the palladium-catalyzed Heck reaction of 3-bromopyridineand 1-aza-5-vinylbicyclo[3.3.0]octane. Typically, procedures similar tothose set forth in Frank et al., J. Org. Chem. 43: 2947 (1978) and Maleket al., J. Org. Chem. 47: 5395 (1982) can be used. Catalysts such aspalladium (II) acetate and ligands such as tri-o-tolylphosphine can beused in a solvent such as acetonitrile using triethylamine as a base.The aforementioned 1-aza-5-vinylbicyclo[3.3.0]octane can be prepared bythe addition of 1,2,3,5,6,7-hexahydropyrroliziniun perchlorate to asolution of vinylmagnesium bromide (commercially available from AldrichChemical Company).

In a similar approach, cis-olefinic compounds such as(Z)-5-(2-(3-pyridyl)vinyl)-1-azabicyclo[3.3.0]octane can be prepared bythe selective hydrogenation of the corresponding alkynyl compound,5-(2-(5-azabicyclo[3.3.0]octyl)ethynyl)pyridine using Lindlar's catalyst(palladium on calcium carbonate) as described by Lindlar et al. Org.Syn. 46: 89 (1966).

Related compounds such as5-(2-(3-pyridyl)ethyl)-1-azabicyclo[3.3.0]octane can be prepared byhydrogenation of the corresponding ethynyl or vinyl compound, namely5-(2-(5-azabicyclo[3.3.0]octyl)ethynyl)pyridine or5-(2-(5-azabicyclo[3.3.0]octyl)vinyl)pyridine, using a catalyst such aspalladium on carbon.

The manner in which certain 5-substituted-pyridyl ethynyl azabicycliccompounds possessing a 1-azabicyclo[3.3.0]octane moiety are synthesizedcan vary. In one approach, compounds such as5-(2-(5-azabicyclo[3.3.0]octyl)ethynyl)-3-cyclopentyloxypyridine can beprepared by the palladium-catalyzed Sonagashira coupling (Thorand et al,supra) of 5-cyclopentyloxy-3-bromopyridine and1-aza-5-ethynylbicyclo[3.3.0]octane. Catalysts, such as copper (I)iodide and bis(triphenylphosphine)palladium dichloride, andtriethylamine as a base in dichloromethane as a solvent can be used. Therequired synthetic intermediate, 1-aza-5-ethynylbicyclo[3.3.0]octane,can be prepared as described above. The aforementioned5-cyclopentyloxy-3-bromopyridine can be prepared by heating3,5-dibromopyridine with cyclopentanol in the presence of sodium in asolvent such as N-methyl-pyrrolidinone, using copper powder as acatalyst. Techniques similar to those reported by Comins et al., J. Org.Chem. 55: 69 (1990) and Den Hertog et al., Rec. Trav. Chim. Pays-Bas.74: 1171 (1955) can beused.

The manner in which certain 5-substituted-pyridyl vinyl azabicycliccompounds of the present invention are synthesized can vary. In oneapproach, compounds such as(E)-5-(2-(5-azabicyclo[3.3.0]octyl)vinyl)-3-cyclopentyloxypyridine canbe synthesized by the palladium catalyzed Heck reaction of5-cyclopentyloxy-3-bromopyridine and 1-aza-5-vinylbicyclo[3.3.0]octane,as previously described. The aforementioned1-aza-5-vinylbicyclo[3.3.0]octane can be prepared by the addition of1,2,3,5,6,7-hexahydropyrroliziniun perchlorate to a solution ofvinylmagnesium bromide, as described above.

The manner in which certain pyrimidinyl ethynyl azabicyclic compoundspossessing a 1-azabicyclo[3.3.0]octane moiety are synthesized can vary.In one approach, compounds such as5-(2-(5-azabicyclo[3.3.0]octyl)ethynyl)pyrimidine can be prepared by thepalladium-catalyzed Sonagashira coupling of 5-bromopyrimidine(commercially available from Aldrich Chemical Company) and1-aza-5-ethynylbicyclo[3.3.0]octane. Catalysts, such as copper (I)iodide and bis(triphenylphosphine)palladium dichloride, andtriethylamine as a base in dichloromethane as a solvent can be used. Therequired synthetic intermediate, 1-aza-5-ethynylbicyclo[3.3.0]octane canbe prepared according to the synthetic methods described previously.

The manner in which certain pyrimidinyl vinyl azabicyclic compounds ofthe present invention are synthesized can vary. In one approach,compounds such as (E)-5-(2-(5-azabicyclo[3.3.0]octyl)vinyl)pyrimidinecan be synthesized by the palladium-catalyzed Heck reaction of1-aza-5-vinylbicyclo[3.3.0]octane and 5-bromopyrimidine. Theaforementioned 1-aza-5-vinylbicyclo[3.3.0]octane can be prepared by theaddition of 1,2,3,5,6,7-hexahydropyrroliziniun perchlorate to a solutionvinylmagnesium bromide, as described above.

Related compounds such as(E)-5-(2-(5-azabicyclo[3.3.0]octyl)ethyl)pyrimidine can be prepared bycatalytic hydrogenation of(E)-5-(2-(5-azabicyclo[3.3.0]octyl)vinyl)pyrimidine or5-(2-(5-azabicyclo[3.3.0]octyl)ethynyl)pyrimidine, using a catalyst suchas palladium on carbon.

The present invention relates to a method for providing prevention of acondition or disorder to a subject susceptible to such a condition ordisorder, and for providing treatment to a subject suffering therefrom.For example, the method comprises administering to a patient an amountof a compound effective for providing some degree of prevention of theprogression of a CNS disorder (i.e., provide protective effects),amelioration of the symptoms of a CNS disorder, and amelioration of therecurrence of a CNS disorder. The method involves administering aneffective amount of a compound selected from the general formulae, whichare set forth hereinbefore. The present invention relates to apharmaceutical composition incorporating a compound selected from thegeneral formulae, which are set forth hereinbefore. Optically activecompounds can be employed as racemic mixtures or as pure enantiomers.The compounds can be employed in a free base form or in a salt form(e.g., as pharmaceutically acceptable salts). Examples of suitablepharmaceutically acceptable salts include inorganic acid addition saltssuch as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate;organic acid addition salts such as acetate, galactarate, propionate,succinate, lactate, glycolate, malate, tartrate, citrate, maleate,fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate; saltswith an acidic amino acid such as aspartate and glutamate; alkali metalsalts such as sodium and potassium; alkaline earth metal salts such asmagnesium and calcium; ammonium salt; organic basic salts such astrimethylamine, dibenzylethylenediamine; and salts with a basic aminoacid such as lysine and arginine. The salts may be in some caseshydrates or ethanol solvates. Representative salts are provided asdescribed in U.S. Pat. No. 5,597,919 to Dull et al., U.S. Pat. No.5,616,716 to Dull et al. and U.S. Pat. No. 5,663,356 to Ruecroft et al.,the disclosures of which are incorporated herein by reference in theirentirety.

Compounds of the present invention are useful for treating those typesof conditions and disorders for which other types of nicotinic compoundshave been proposed as therapeutics. See, for example, Williams et al.,Drug News Perspec. 7(4):205 (1994), Arneric et al., CNS Drug Rev. 1(1):1(1995), Arneric et al., Exp. Opin. Invest. Drugs 5(1):79 (1996),Bencherif et al., J. Pharmacol. Exp. Ther. 279:1413 (1996), Lippiello etal., J. Pharmacol. Exp. Ther. 279:1422 (1996), Damaj et al., J.Pharmacol. Exp. Ther. 291:390 (1999); Chiari et al., Anesthesiology91:1447 (1999); Lavand'homme and Eisenbach, Anesthesiology 91:1455(1999); Holladay et al., J. Med. Chem 40(28):4169 (1997), Bannon et al.,Science 279:77 (1998), PCT WO 94/08992, PCT WO 96/31475, and U.S. Pat.No. 5,583,140 to Bencherif et al., U.S. Pat. No. 5,597,919 to Dull etal., and U.S. Pat. No. 5,604,231 to Smith et al., the disclosures ofwhich are incorporated herein by reference in their entirety. Compoundsof the present invention can be used as analgesics, to treat ulcerativecolitis, inflammatory and auto-immune diseases (e.g., arthritis,cholangitis, stomatitis, pouchitis, viral pneumonitis), to treat avariety of neurodegenerative diseases, and to treat convulsions such asthose that are symptomatic of epilepsy. CNS disorders which can betreated in accordance with the present invention include pre-seniledementia (early onset Alzheimer's disease), senile dementia (dementia ofthe Alzheimer's type), HIV-dementia, multiple cerebral infarcts,Parkinsonism including Parkinson's disease, Pick's disease, Huntington'schorea, tardive dyskinesia, hyperkinesia, mania, attention deficitdisorder, anxiety, depression, mild cognitive impairment, dyslexia,schizophrenia and Tourette's syndrome. Compounds of the presentinvention also can be used to treat conditions such as syphillis andCreutzfeld-Jakob disease. The compounds of the present invention alsocan be appropriately synthesized and used as or within pharmaceuticalcompositions that are used as diagnostic probes.

The pharmaceutical composition also can include various other componentsas additives or adjuncts. Exemplary pharmaceutically acceptablecomponents or adjuncts which are employed in relevant circumstancesinclude antioxidants, free-radical scavenging agents, peptides, growthfactors, antibiotics, bacteriostatic agents, immunosuppressives,anticoagulants, buffering agents, anti-inflammatory agents,anti-pyretics, time-release binders, anaesthetics, steroids, vitamins,minerals and corticosteroids. Such components can provide additionaltherapeutic benefit, act to affect the therapeutic action of thepharmaceutical composition, or act towards preventing any potential sideeffects which may be imposed as a result of administration of thepharmaceutical composition. In certain circumstances, a compound of thepresent invention can be employed as part of a pharmaceuticalcomposition with other compounds intended to prevent or treat aparticular disorder.

The manner in which the compounds are administered can vary. Thecompounds can be administered by inhalation (e.g., in the form of anaerosol either nasally or using delivery articles of the type set forthin U.S. Pat. No. 4,922,901 to Brooks et al., the disclosure of which isincorporated herein in its entirety); topically (e.g., in lotion form);orally (e.g., in liquid form within a solvent such as an aqueous ornon-aqueous liquid, or within a solid carrier); intravenously (e.g.,within a dextrose or saline solution); as an infusion or injection(e.g., as a suspension or as an emulsion in a pharmaceuticallyacceptable liquid or mixture of liquids); intrathecally;intracerebroventricularly; or transdermally (e.g., using a transdermalpatch). Although it is possible to administer the compounds in the formof a bulk active chemical, it is preferred to present each compound inthe form of a pharmaceutical composition or formulation for efficientand effective administration. Exemplary methods for administering suchcompounds will be apparent to the skilled artisan. For example, thecompounds can be administered in the form of a tablet, a hard gelatincapsule or as a time-release capsule. As another example, the compoundscan be delivered transdermally using the types of patch technologiesavailable from Novartis and Alza Corporation. The administration of thepharmaceutical compositions of the present invention can be intermittentor at a gradual, continuous, constant or controlled rate to awarm-blooded animal (e.g., a mammal such as a mouse, rat, cat, rabbit,dog, pig, cow, or monkey), but advantageously is administered preferablyto a human being. In addition, the time of day and the number of timesper day that the pharmaceutical formulation is administered can vary.Preferable administration is such that the active ingredients of thepharmaceutical formulation interact with receptor sites within the bodyof the subject that affect the functioning of the CNS. Morespecifically, in treating a CNS disorder, preferable administration isdesigned to optimize the effect upon those relevant receptor subtypesthat have an effect upon the functioning of the CNS, while minimizingthe effects upon muscle-type receptor subtypes. Other suitable methodsfor administering the compounds of the present invention are describedin U.S. Pat. No. 5,604,231 to Smith et al.

The appropriate dose of the compound is that amount effective to preventoccurrence of the symptoms of the disorder or to treat some symptoms ofthe disorder from which the patient suffers. By “effective amount”,“therapeutic amount” or “effective dose” is meant that amount sufficientto elicit the desired pharmacological or therapeutic effects, thusresulting in effective prevention or treatment of the disorder. Thus,when treating a CNS disorder, an effective amount of compound is anamount sufficient to pass across the blood-brain barrier of the subject,to bind to relevant receptor sites in the brain of the subject and toactivate relevant nicotinic receptor subtypes (e.g., provideneurotransmitter secretion, thus resulting in effective prevention ortreatment of the disorder). Prevention of the disorder is manifested bydelaying the onset of the symptoms of the disorder. Treatment of thedisorder is manifested by a decrease in the symptoms associated with thedisorder or an amelioration of the recurrence of the symptoms of thedisorder.

The effective dose can vary, depending upon factors such as thecondition of the patient, the severity of the symptoms of the disorder,and the manner in which the pharmaceutical composition is administered.For human patients, the effective dose of typical compounds generallyrequires administering the compound in an amount sufficient to activaterelevant receptors to effect neurotransmitter (e.g., dopamine) release,but the amount should be insufficient to induce effects on skeletalmuscles and ganglia to any significant degree. The effective dose ofcompounds will of course differ from patient to patient, but in generalincludes amounts starting where CNS effects or other desired therapeuticeffects occur but below the amount where muscular effects are observed.

The compounds useful according to the method of the present inventionhave the ability to pass across the blood-brain barrier of the patient.As such, these compounds have the ability to enter the central nervoussystem of the patient. The log P values of typical compounds, which areuseful in carrying out the present invention, are generally greater thanabout −0.5, often are greater than about 0, and frequently are greaterthan about 0.5. The log P values of such typical compounds generally areless than, about 3, often are less than about 2, and frequently are lessthan about 1. Log P values provide a measure of the ability of acompound to pass across a diffusion barrier, such as a biologicalmembrane, including the blood brain barrier. See, for example, Hansch etal., J. Med. Chem. 11:1 (1968).

The compounds useful according to the method of the present inventionhave the ability to bind to, and in most circumstances, cause activationof, nicotinic dopaminergic receptors of the brain of the patient. Assuch, these compounds have the ability to express nicotinic pharmacologyand, in particular, to act as nicotinic agonists. The receptor bindingconstants of typical compounds useful in carrying out the presentinvention generally exceed about 0.1 nM, often exceed about 1 nM, andfrequently exceed about 10 nM. The receptor binding constants of certaincompounds are less than about 100 μM, often are less than about 10 μMand frequently are less than about 5 μM; and of preferred compoundsgenerally are less than about 2.5 μM, sometimes are less than about 1μM, and can be less than about 100 nM. Receptor binding constantsprovide a measure of the ability of the compound to bind to half of therelevant receptor sites of certain brain cells of the patient. See, forexample, Cheng et al., Biochem. Pharmacol. 22:3099 (1973).

The compounds useful according to the method of the present inventionhave the ability to demonstrate a nicotinic function by effectivelyactivating neurotransmitter secretion from nerve ending preparations(i.e., synaptosomes). As such, these compounds have the ability toactivate relevant neurons to release or secrete acetylcholine, dopamine,and other neurotransmitters. Generally, typical compounds useful incarrying out the present invention provide for the activation ofdopamine secretion in amounts of at least one third, typically at leastabout 10 times less, frequently at least about 100 times less, andsometimes at least about 1,000 times less than those required foractivation of muscle-type nicotinic receptors. Certain compounds of thepresent invention can provide secretion of dopamine in an amount whichis comparable to that elicited by an equal molar amount of(S)-(−)-nicotine.

The compounds of the present invention, when employed in effectiveamounts in accordance with the method of the present invention, areselective to certain relevant nicotinic receptors, but do not causesignificant activation of receptors associated with undesirable sideeffects at concentrations at least greater than those required foractivation of dopamine release. By this is meant that a particular doseof compound resulting in prevention and/or treatment of a CNS disorderis essentially ineffective in eliciting activation of certainganglionic-type nicotinic receptors at concentration higher than 5times, preferably higher than 100 times, and more preferably higher than1,000 times than those required for activation of dopamine release. Thisselectivity of certain compounds of the present invention against thoseganglionic-type receptors responsible for cardiovascular side effects isdemonstrated by a lack of the ability of those compounds to activatenicotinic function of adrenal chromaffin tissue at concentrationsgreater than those required for activation of dopamine release.

Compounds of the present invention, when employed in effective amountsin accordance with the method of the present invention, are effectivetowards providing some degree of prevention of the progression of CNSdisorders, amelioration of the symptoms of CNS disorders, andamelioration to some degree of the recurrence of CNS disorders. However,such effective amounts of those compounds are not sufficient to elicitany appreciable side effects, as demonstrated by increased effectsrelating to skeletal muscle. As such, administration of certaincompounds of the present invention provides a therapeutic window inwhich treatment of certain CNS disorders is provided and certain sideeffects are avoided. That is, an effective dose of a compound of thepresent invention is sufficient to provide the desired effects upon theCNS but is insufficient (i.e., is not at a high enough level) to provideundesirable side effects. Preferably, effective administration of acompound of the present invention resulting in treatment of CNSdisorders occurs upon administration of less than ⅕, and often less than1/10, that amount sufficient to cause certain side effects to anysignificant degree.

The pharmaceutical compositions of the present invention can be employedto prevent or treat certain other conditions, diseases and disorders.Exemplary of such diseases and disorders include inflammatory boweldisease, pouchitis, acute cholangitis, aphthous stomatitis, arthritis(e.g., rheumatoid arthritis and osteoarthritis), neurodegenerativediseases, cachexia secondary to infection (e.g., as occurs in AIDS,AIDS-related complex and neoplasia), as well as those indications setforth in PCT WO 98/25619. The pharmaceutical compositions of the presentinvention can be employed in order to ameliorate many of the symptomsassociated with those conditions, diseases and disorders. Thus,pharmaceutical compositions of the present invention can be used intreating genetic diseases and disorders, in treating auto-immunedisorders such as lupus, as anti-infectious agents (e.g., for treatingbacterial, fungal and viral infections, as well as the effects, such assepsis, of otber types of toxins), as anti-inflammatory agents (e.g.,for treating acute cholangitis, aphthous stomatitis, asthma, andulcerative colitis), and as inhibitors of cytokine release (e.g., as isdesirable in the treatment of cachexia, inflammation, neurodegenerativediseases, viral infection, and neoplasia). The compounds of the presentinvention can also be used as adjunct therapy in combination withexisting therapies in the management of the aforementioned types ofdiseases and disorders. In such situations, preferable administration issuch that the active ingredients of the pharmaceutical formulation actto optimize effects upon abnormal cytokine production, while minimizingeffects upon receptor subtypes such as those that are associated withmuscle and ganglia. Preferable administration is such that activeingredients interact with regions where cytokine production is affectedor occurs. For the treatment of such conditions or disorders, compoundsof the present invention are very potent (i.e., affect cytokineproduction and/or secretion at very low concentrations) and are veryefficacious (i.e., significantly inhibit cytokine production and/orsecretion to a relatively high degree).

Most preferably, effective doses are at very low concentrations, wheremaximal effects are observed to occur. Concentrations, determined as theamount of compound per volume of relevant tissue, typically provide ameasure of the degree to which that compound affects cytokineproduction. Typically, the effective dose of compounds generallyrequires administering the compound in an amount of less than 5 mg/kg ofpatient weight. Often, the compounds of the present invention areadministered in an amount from less than about 1 mg/kg patient weightand usually less than about 100 μg/kg of patient weight, but frequentlybetween about 10 μg to less than 100 μg/kg of patient weight. Forcompounds of the present invention that do not induce effects onmuscle-type nicotinic receptors at low concentrations, the effectivedose is less than 5 mg/kg of patient weight; often such compounds areadministered in an amount from 50 μg to less than 5 mg/kg of patientweight. The foregoing effective doses typically represent that amountadministered as a single dose, or as one or more doses administered overa 24-hour period.

For human patients, the effective dose of typical compounds generallyrequires administering the compound in an amount of at least about 1,often at least about 10, and frequently at least about 25 μg/24hr/patient. For human patients, the effective dose of typical compoundsrequires administering the compound which generally does not exceedabout 1, often does not exceed about 0.75, often does not exceed about0.5, and frequently does not exceed about 0.2 mg/24 hr/patient. Inaddition, administration of the effective dose is such that theconcentration of the compound within the plasma of the patient normallydoes not exceed 500 pg/mL, often does not exceed 300 pg/mL, andfrequently does not exceed 100 pg/mL.

When employed in such a manner, compounds of the present invention aredose dependent, and, as such, cause inhibition of cytokine productionand/or secretion when employed at low concentrations but do not exhibitthose inhibiting effects at higher concentrations. Compounds of thepresent invention exhibit inhibitory effects upon cytokine productionand/or secretion when employed in amounts less than those amountsnecessary to elicit activation of relevant nicotinic receptor subtypesto any significant degree.

The following examples are provided to illustrate the present inventionand should not be construed as limiting the scope thereof. In theseexamples, all parts and percentages are by weight, unless otherwisenoted. Reaction yields are reported in mole percentages.

EXAMPLES Assays

Determination of Binding to Relevant Receptor Sites

Binding of the compounds to relevant receptor sites was determined inaccordance with the techniques described in U.S. Pat. No. 5,597,919 toDull et al. Inhibition constants (K_(i) values), reported in nM, werecalculated from the IC₅₀ values using the method of Cheng et al.,Biochem. Pharmacol. 22:3099 (1973). Low binding constants indicate thatthe compounds of the present invention exhibit good high affinitybinding to certain CNS nicotinic receptors.

Example 1

Sample No. 1 is (2S)-(2E)-2-(3-prop-1-(3-pyridyl)-1-enyl)pyrrolidinehemigalactarate (or (S)-(E)-3-(3-pyrrolidin-2-yl-prop-1-enyl)pyridinehemigalactarate), which was prepared in accordance with the followingtechniques:

(2S)-N-(tert-Butoxycarbonyl)-2-(hydroxymethyl)pyrrolidine

Under a nitrogen atmosphere, an ice-cold stirring solution of(2S)-2-pyrrolidinemethanol (3.00 g, 29.7 mmol, Aldrich ChemicalCompany), triethylamine (4.3 mL, 3.12 g, 30.9 mmol) in drydichloromethane (50 mL) was treated in portions over 10 min withdi-tert-butyl dicarbonate (7.11 g, 32.6 mmol). The solution was stirredand allowed to warm to ambient temperature overnight. Saturated aqueousNaHCO₃ solution (25 mL) was added, and the mixture was extracted withCHCl₃ (3×50 mL). The combined extracts were dried (K₂CO₃), filtered andconcentrated under vacuum producing 5.50 g (92.1%) of a thick, colorlesssyrup.

(2S)-N-(tert-Butoxycarbonyl)-2-(iodomethyl)pyrrolidine

Under a nitrogen atmosphere, a solution of diethyl azodicarboxylate(4.699 g, 26.98 mmol) in dry tetrahydrofuran (THF) (15 mL) was addeddrop-wise to an ice-cold stirring solution of(2S)-N-(tert-butoxycarbonyl)-2-(hydroxymethyl)pyrrolidine (5.37 g, 26.7mmol), iodine (3.42 g, 13.5 mmol) and triphenylphosphine (7.069 g, 26.95mmol) in dry THF (50 mL). The mixture was stirred and allowed to warm toambient temperature overnight. The mixture was concentrated on a rotaryevaporator and then the residue was stirred with 5% aqueous Na₂S₂O₃ (50mL). After stirring for 30 min, the mixture was extracted withdichloromethane (4×25 mL). The combined dichloromethane extracts weredried (Na₂SO₄), filtered and concentrated. The residue was repeatedlycrystallized (three to four times) from dry ether and finally fromheptane to give 3.20 g (38.6%) of product.

(2S)-N-(tert-Butoxycarbonyl)-2-allylpyrrolidine

Under a nitrogen atmosphere, a solution of vinylmagnesium bromide, 1.0 Min tetrahydrofuran (2.0 mL, 2.0 mmol) was slowly added to a suspensionof copper(I) iodide (244.9 mg, 1.28 mmol) in dry diethyl ether (10 mL)at −78° C. Upon completion of the addition, the mixture was warmed to−36° C. for 5 min and was then cooled to −78° C. A solution of(2S)-N-(tert-butoxycarbonyl)-2-(iodomethyl)pyrrolidine (200.0 mg, 0.64mmol) in dry diethyl ether (5 mL) was added over a period of 10 min. Thereaction mixture was warmed to −36° C. and was stirred at −36° C. for 6h. The resulting dark mixture was treated with saturated aqueous NH₄Clsolution (5 mL) and was stirred while warming to ambient temperature.The reaction mixture was extracted with diethyl ether (4×10 mL). Thecombined ether extracts were dried (Na₂SO₄), filtered and concentratedunder vacuum to yield a pale-yellow oil (200 mg). The product waspurified by column chromatography, eluting with hexane:ethyl acetate(1:1). Fractions containing the product were combined and concentratedunder vacuum to afford 100 mg (73.6%) of an oil.

(2S)-(2E)-N-(tert-Butoxycarbonyl)-2-(3-prop-1-(3-pyridyl)-1-enyl)pyrrolidine

A thick-walled glass pressure tube was charged with(2S)-N-(tert-butoxycarbonyl)-2-allylpyrrolidine (100.0 mg, 0.47 mmol),3-bromopyridine (112.3 mg, 0.71 mmol), palladium(II) acetate (10.63 mg,0.047 mmol), tri-o-tolylphosphine (14.42 mg, 0.074 mmol), triethylamine(1.0 mL, 7.2 mmol) and acetonitrile (10 mL). The tube was sealed and thereaction mixture was stirred and heated at 110-120° C. for 8 h. Aftercooling, the tube contents were added to a stirring, saturated aqueousNaHCO₃ solution. The mixture was extracted with CHCl₃ (4×20 mL). Thecombined CHCl₃ extracts were dried (K₂CO₃), filtered and concentratedunder vacuum to give a thick, dark syrup (500 mg). The product waspurified by column chromatography, eluting with a gradient of ethylacetate:hexane (20:80 to 50:50). Fractions containing the product werecombined and concentrated under vacuum to give 75.0 mg (54.9%) of anoil.

(2S)-(2E)-2-(3-Prop-1-(3-pyridyl)-1-enyl)pyrrolidine

Under a nitrogen atmosphere, an ice-cold stirring solution of(2S)-(2E)-N-(tert-butoxycarbonyl)-2-(3-prop-1-(3-pyridyl)-1-enyl)pyrrolidine(50.0 mg, 0.17 mmol) in anisole (1 mL) was treated with trifluoroaceticacid (1 mL). After stirring for 30 min, the solution was treated withsaturated aqueous NaHCO₃ solution, saturated with solid NaCl, andextracted with CHCl₃ (5×10 mL). The combined CHCl₃ extracts were dried(K₂CO₃), filtered and concentrated on a rotary evaporator to give athick, dark syrup. The product was purified by column chromatography,eluting with a gradient of chloroform:methanol (up to 9:1), containing1% Et₃N. Selected fractions were combined and concentrated under vacuumto give 20.0 mg (61.3%) of a pale, light-yellow oil.

(2S)-(2E)-2-(3-Prop-1-(3-pyridyl)-1-enyl)pyrrolidine hemigalactarate

Galactaric acid (10.0 mg, 0.048 mmol) was added to a solution of(2S)-(2E)-2-(3-prop-1-(3-pyridyl)-1-enyl)pyrrolidine (18.0 mg, 0.096mmol) in absolute ethanol (1 mL). The mixture was heated at 60° C. andsonicated. Water (2-3 drops) was added, and the process was repeated 3-4times producing a clear solution. The solution was filtered andconcentrated; ethanol (2 mL) was added to the residue and removed byrotary evaporation. The resulting solid was dissolved in a minimumamount of ethanol and dry diethyl ether was added, producing a cloudysolution. After standing 2 days at ambient temperature, the resultingsolid was filtered and washed with ether to give 16.6 mg (59.1%) of apale, light-yellow solid, mp 138-141° C.

Sample No. 1 exhibits a K_(i) of 472 nM. The low binding constantindicates that the compound exhibits good high-affinity binding tocertain CNS nicotinic receptors.

Example 2

Sample No. 2 is (S)-(E)-3(2-pyrrolidin-2-ylvinyl)pyridinehemigalactarate, which was prepared in accordance with the followingtechniques:

(S)-N-tert-Butoxycarbonyl-2-formylpyrrolidine

Pyridinium chlorochromate (3.26 g, 15.2 mmol) was added to a solution of(2S)-N-(tert-butoxycarbonyl)-2-(hydroxymethyl)pyrrolidine (2.77 g, 13.8mmol) in dichloromethane (50 mL) and the mixture was stirred at roomtemperature for 12 h. The solvent was removed on a rotary evaporator togive a dark brown gum, which was chromatographed, using ethylacetate:hexane (1:1, v/v) as eluant. Selected fractions containing theproduct were combined and concentrated on a rotary evaporator to give1.45 g (52.9% yield) of a colorless oil.

(S)-(N-tert-Butoxycarbonyl)-2-vinylpyrrolidine

The title compound was prepared according to the procedure of Corey etal., J. Amer. Chem. Soc. 104: 4724 (1982). Thus, n-butyllithium (0.70mL, 2.5 M solution in hexane) was added to a stirred ice-cold solutionof methyl triphenylphosphonium bromide (634.7 mg, 1.776 mmol) inanhydrous diethyl ether (10 mL). The mixture was allowed to warm to roomtemperature, stirred for 3 h, and was then added dropwise via a cannulato a cold (−78° C.) solution of(2S)-N-(tert-butoxycarbonyl)-2-formylpyrrolidine (350 mg, 1.77 mmol) inanhydrous diethyl ether (10 mL) under a nitrogen atmosphere. Thereaction mixture was allowed to warm to room temperature and stirred for16 h. Saturated aqueous NH₄Cl solution (2 mL) was added, the mixturestirred for 10 min and extracted with ethyl acetate (3×15 mL). Thecombined ethyl acetate extracts were dried (K₂CO₃), filtered andconcentrated on a rotary evaporator to give a viscous brown oil, whichwas chromatographed, using ethyl acetate:hexane (1:9, v/v) as eluant.Selected fractions containing the product were combined and concentratedunder vacuum to afford 310 mg (89.5% yield) of a colorless oil.

(S)-(E)-N-(tert-Butoxycarbonyl)-2-(2-(3-pyridyl)vinyl)pyrrolidine

In a sealed pressure tube under a nitrogen atmosphere, 3-bromopyridine(264.67 mg, 1.675 mmol), (2S)-N-tert-butoxycarbonyl-2-vinylpyrrolidine(300 mg, 1.52 mmol), tri-o-tolylphosphine (46.82 mg, 0.153 mmol),palladium(II) acetate (34.53 mg, 0.15 mmol), triethylamine (2 mL) andacetonitrile (20 mL) were stirred at 90° C. for 14 h. The tube wascooled and the contents were slowly poured into a stirred saturatedaqueous NaHCO₃ solution (20 mL) and extracted with chloroform (4×20 mL).The combined chloroform extracts were dried (K₂CO₃), filtered andconcentrated under vacuum to give 500 mg of a viscous dark oil, whichwas chromatographed with an ethyl acetate:hexane gradient (1:4 to 1:1,v/v) as eluant. Selected fractions containing the product were combinedand concentrated on a rotary evaporator to give 310 mg (84.0% yield) ofpale-yellow oil.

(S)-(E)-3-(2-Pyrrolidin-2-ylvinyl)pyridine

Under a nitrogen atmosphere, trifluoroacetic acid (1 mL) was addeddropwise to a stirred ice-cold solution of(2S)-N-(tert-butoxycarbonyl)-2-(2-(3-pyridyl)vinyl)pyrrolidine (280 mg,1.02 mmol) in anisole (2 mL). The reaction mixture was allowed to warmto room temperature, stirred for 16 h, then neutralized with saturatedaqueous NaHCO₃ solution, saturated with solid NaCl and extracted withchloroform (5×10 mL). The combined chloroform extracts were dried(K₂CO₃), filtered and concentrated on a rotary evaporator to give aviscous dark oil, which was chromatographed with chloroform:methanol(9:1, v/v) and 1% triethylamine as eluant. Selected fractions containingthe product were combined and concentrated on a rotary evaporator togive 130 mg (73.1% yield) of a colorless oil.

(S)-(E)-3-(2-Pyrrolidin-2-ylvinyl)pyridine hemigalactarate

To a stirred solution of (2S)-3-(2-pyrrolidin-2-ylvinyl)pyridine (120mg, 0.689 mmol) in ethanol (2 mL), galactaric acid (72.4 mg, 0.344 mmol)was added. The mixture was heated at 70° C., sonicated and then water(1-2 drops) was added; this process was repeated until most of the soliddissolved. The remaining insoluble material was removed by filtration.To the filtrate anhydrous diethyl ether was added dropwise until itbecame cloudy. After 16 h at 4° C. a precipitate was formed; this wasfiltered and vacuum dried to give 120 mg (61.9% yield) of product as alight brown solid.

Sample No. 2 exhibits a K_(i) of 306 nM. The low binding constantindicates that the compound exhibits good high-affinity binding tocertain CNS nicotinic receptors.

Example 3

Sample No. 3 is (S)-5-(2-Pyrrolidin-2-ylethynyl)pyrimidine, which wasprepared according to the following techniques:

(2S)-N-(tert-Butoxycarbonyl)-2-ethynylpyrrolidine

A solution of (2S)-N-(tert-butoxycarbonyl)-2-formylpyrrolidine (4.0 g,20 mmole), carbon tetrabromide (6.67 g, 20.1 mmole) andtriphenylphosphine (5.26 g, 20.1 mmole) in methylene chloride (100 mL)was stirred at ambient temperature under a nitrogen atmosphere for 24hours. The mixture was concentrated, then purified by chromatography,using (1:1) ethyl acetate:hexane as eluant to provide the desiredproduct as an oil. The product was dissolved in dry tetrahydrofuran (50mL) and cooled to −78° C. A solution of n-butyllithium (50.25 mL, 20.1mmole, 2.5 M solution in hexanes) was added and the mixture was stirredat −78° C. for 1 h. The material was quenched with water (20 mL) andextracted with ethyl acetate (3×50 mL). The combined extracts were dried(K₂CO₃), concentrated and purified by chromatography, using (1:1) ethylacetate:hexane as eluant to provide (3.10 g, 91%) of a colorless oil.

(S)-N-(tert-Butoxycarbonyl)-2-(2-(5-pyrimidinyl)ethynyl)pyrrolidine

Triethylamine (10 mL) was degassed by bubbling argon over a period of 30min. (S)-N-tert-Butoxycarbonyl-2-ethynylpyrrolidine (0.300 g, 5.12mmol), tetrakis(triphenylphosphine)palladium (0.180 g, 0.1 mmol),palladium(II) acetate (0.0346 g, 0.10 mmol), copper (I) iodide (6.25 mg,0.033 mmol) and 5-bromo-pyrimidine (0.4867 g, 3.07 mmol) were added. Themixture was heated at 110° C. for 9 h, then cooled to room temperatureand concentrated by rotary evaporation. The residue was dissolved inchloroform (50 mL) and the organic phase washed with water (25 mL),saturated aqueous NaHCO₃ solution (3×20 mL) and water (25 mL), thendried (MgSO₄), filtered and concentrated by rotary evaporation. Thecrude product was purified by column chromatography, eluting with ethylacetate/hexane (1/1, v/v). Selected fractions containing the productwere concentrated via rotary evaporation to give 0.310 g (74%) of ayellow oil.

(S)-5-(Pyrrolidin-2-ylethynyl)pyrimidine

A^(n) ice-cold stirred solution(S)-N-tert-butoxycarbonyl-2-(3-pyrimidinyl)ethynyl-1-pyrrolidine (310mg, 2.3 mmol) in ethyl acetate (25 mL) was treated with hydrochloricacid (1 mL). The mixture was stirred for 10 min at 0-5° C., then for 3 hat room temperature. The layers were separated and the pH of the aqueousportion was brought to 12 with 1N NaOH. The aqueous phase was extractedwith ethyl acetate (2×25 mL). The combined organic phases were washedwith brine (5 mL), then dried (MgSO₄), filtered and concentrated byrotary evaporation. The crude product was purified by columnchromatography on silica gel, eluting with chloroform/methanol (90/10,v/v). Selected fractions containing the product were concentrated viarotary evaporation to give 0.046 g of a yellow oil.

Sample No. 3 exhibits a K_(i) of 46 nM. The low binding constantindicates that the compound exhibits good high-affinity binding tocertain CNS nicotinic receptors.

Example 4

Sample No. 4 is (R)-5-(2-Pyrrolidin-2-ylethynyl)pyrimidine, which wasprepared according to the methods described for Example 3 using thecorresponding (R)-N-(tert-butoxycarbonyl)-2-formylpyrrolidineenantiomer.

Sample No. 4 exhibits a K_(i) of 342 nM. The low binding constantindicates that the compound exhibits good high-affinity binding tocertain CNS nicotinic receptors.

Example 5

Sample No. 5 is (S)-5-(2-Pyrrolidin-2-ylethynyl)pyridine, which wasprepared according to the following techniques:

(S)-N-(tert-Butoxycarbonyl)-2-(2-(3-pyridyl)ethynyl)pyrrolidine

Triethylamine (10 mL) was degassed by bubbling argon over a period of 30min. (S)-N-(tert-butoxycarbonyl)-2-ethynylpyrrolidine (1.00 g, 5.12mmol), tetrakis(triphenylphosphine)palladium (0.296 g, 0.256 mmol),palladium(II) acetate (0.0575 g, 0.256 mmol), copper (I) iodide (16.2mg, 0.085 mmol) and 5-bromopyridine (2.43 g, 15.4 mmol) were added. Themixture was heated at 60° C. for 24 h, then cooled to room temperatureand concentrated by rotary evaporation. The residue was dissolved inchloroform (50 mL) and the organic phase washed sequentially with water(25 mL), saturated aqueous NaHCO₃ solution (3×20 mL) and water (25 mL).The solution was then dried (MgSO₄), filtered and concentrated by rotaryevaporation. The crude product was purified by column chromatography onsilica gel, eluting with ethyl acetate/hexane (1/1, v/v). Selectedfractions containing the product were concentrated via rotaryevaporation to give 1.00 g (71%) of a yellow oil.

(S)-2-(2-(3-Pyridyl)ethynyl)pyrrolidine

An ice-cold stirred solution(S)-N-(tert-butoxycarbonyl)-2-(2-(3-pyridyl)ethynyl)pyrrolidine (300 mg,1.10 mmol) in ethyl acetate (25 mL) was treated with concentratedhydrochloric acid (1 mL). The mixture was stirred for 10 min at 0-5° C.,then for 3 h at room temperature. The layers were separated and the pHof the aqueous portion was brought to 12 with 1N NaOH. The aqueous phasewas extracted with ethyl acetate (2×25 mL). The combined organic phaseswere washed with brine (5 mL), then dried (MgSO₄), filtered andconcentrated by rotary evaporation. The crude product was purified bycolumn chromatography on silica gel, eluting with chloroform/methanol(90/10, v/v). Selected fractions containing the product wereconcentrated via rotary evaporation to give 0.120 g of a yellow oil.

Sample No. 5 exhibits a K_(i) of 12 nM. The low binding constantindicates that the compound exhibits good high-affinity binding tocertain CNS nicotinic receptors.

Example 6

Sample No. 6 is (R)-5-(2-Pyrrolidin-2-ylethynyl)pyridine, which wasprepared according to the methods described for Example 5 using thecorresponding (R)-N-(tert-butoxycarbonyl)-2-formylpyrrolidine and3-bromopyridine.

Sample No. 6 exhibits a K_(i) of 450 nM. The low binding constantindicates that the compound exhibits good high-affinity binding tocertain CNS nicotinic receptors.

Example 7

Sample No. 7 is (S)-3-isopropoxy-5-(pyrrolidin-2-ylethynyl)pyridinehemigalactarate, which was prepared in accordance with the followingtechniques:

3-Bromo-5-isopropoxypyridine

This product was prepared using the procedure described in patent WO0075110.

(S)-N-(tert-Butoxycarbonyl)-2-ethynyl-1-pyrrolidine

This product was prepared using the procedure described by Trybulski etal., J. Med. Chem. 33(12):3190 (1990).

(S)-N-(tert-Butoxycarbonyl)-2-(5-isopropoxy-3-pyridyl)ethynyl-1-pyrrolidine

Diisopropylethylamine (10 mL) was degassed by bubbling argon over aperiod of 30 min. (S)-N-tert-Butoxycarbonyl-2-ethynyl-1-pyrrolidine(0.391 g, 2 mmol), tetrakis(triphenylphosphine)palladium (0.115 g, 0.1mmol), palladium(II) acetate (0.022 g, 0.1 mmol), copper (I) iodide(6.25 mg, 0.033 mmol) and 3-bromo-5-isopropoxypyridine (0.87 g, 4 mmol)were added. The mixture was heated at 110° C. for 15 h, then cooled toroom temperature and concentrated by rotary evaporation. The residue wasdissolved in ethyl acetate (50 mL) and the organic phase washed withwater (25 mL), saturated aqueous NaHCO₃ solution (2×25 mL) and water (25mL), then dried (MgSO₄), filtered and concentrated by rotaryevaporation. The crude product was purified by column chromatography,eluting with ethyl acetate/cyclohexane (20/80, v/v). Selected fractionscontaining the product were concentrated via rotary evaporation andjoined to the product of another similar experiment to give 1.1 g ofcrude product, which was purified by column chromatography, eluting withethyl acetate/cyclohexane (20/80, v/v). Selected fractions containingthe product were concentrated via rotary evaporation to give 0.66 g(17%) of an orange oil.

(S)-3-Isopropoxy-5-(pyrrolidin-2-ylethynyl)pyridine hemigalactarate

An ice-cold stirred solution of(S)-N-(tert-butoxycarbonyl)-2-(5-isopropoxy-3-pyridyl)ethynyl-1-pyrrolidine(660 mg, 1.8 mmol) in dichloromethane (12.5 mL) was treated withtrifluoroacetic acid (2.8 mL). The mixture was stirred for 20 min at0-5° C., then for 3 h at room temperature and concentrated by rotaryevaporation. To the oily residue was added water (20 mL) and the pH wasbrought to 12 with 1N NaOH. The aqueous phase was extracted with ethylacetate (2×25 mL). The combined organic phases were washed with brine (5mL), then dried (MgSO₄), filtered and concentrated by rotaryevaporation. The crude product was purified by column chromatography,eluting with dichloromethane/methanol (90/10, v/v). Selected fractionscontaining the product were concentrated via rotary evaporation to give0.34 g of a yellow oil. To a solution of this oil in a mixture ofmethanol (9 mL) and water (1 mL) was added galactaric acid (155 mg, 0.73mmol). The mixture was stirred and heated until complete dissolution ofthe galactaric acid, then was cooled to room temperature andconcentrated by rotary evaporation to give an oil, which was trituratedin a mixture of ethanol (1 mL) and isopropyl acetate (6 mL). Theresulting solid was filtered, washed with isopropyl acetate, thendiisopropyl ether (2×5 mL) and dried under vacuum at 50° C. to afford380 mg (63%) of an off-white solid.

Sample No. 7 exhibits a K_(i) of 2 nM. The low binding constantindicates that the compound exhibits good high-affinity binding tocertain CNS nicotinic receptors.

Example 8

Sample No. 8 is (S)-3-phenyl-5-(pyrrolidin-2-ylethynyl)pyridinehemigalactarate, which was prepared in accordance with the followingtechniques:

3-Bromo-5-phenylpyridine

This product was prepared using the procedure described in patent WO9837071.

(S)-N-(tert-Butoxycarbonyl)-2-(5-phenyl-3-pyridyl)ethynyl-1-pyrrolidine

Triethylamine (15 mL) was degassed by bubbling argon over a period of 30min. (S)-N-(tert-Butoxycarbonyl)-2-ethynyl-1-pyrrolidine (0.781 g, 4mmol), crude (90% purity) 3-bromo-5-phenylpyridine (1.97 g, 4 mmol),tetrakis(triphenylphosphine) palladium (0.231 g, 0.2 mmol),palladium(II) acetate (0.045 g, 0.2 mmol) and copper (I) iodide (13.3mg, 0.07 mmol) were added. The mixture was heated under reflux for 3 h,then cooled to room temperature and concentrated by rotary evaporation.The residue was dissolved in ethyl acetate (50 mL) and the organic phasewashed with water (2×25 mL), saturated aqueous NaHCO₃ solution (2×25 mL)and water (2×25 mL), then dried (MgSO₄), filtered and concentrated byrotary evaporation. The crude product was purified by columnchromatography, eluting with ethyl acetate/cyclohexane (20/80, v/v).Selected fractions containing the product were concentrated via rotaryevaporation to give 0.7 g (50%) of an orange oil.

(S)-3-Phenyl-5-(pyrrolidin-2-ylethynyl)pyridine hemigalactarate

An ice-cold stirred solution of(S)-N-(tert-butoxycarbonyl)-2-(5-phenyl-3-pyridyl)ethynyl-1-pyrrolidine(0.7 g, 2 mmol) in dichloromethane (15.5 mL) was treated withtrifluoroacetic acid (3.1 mL). The mixture was stirred for 30 min at0-5° C., then for 3 h at room temperature and concentrated by rotaryevaporation. To the oily residue was added water (25 mL) and the pH wasbrought to 12 with 1N NaOH. The aqueous phase was extracted withdichloromethane (3×30 mL). The combined organic phases were washed withbrine (25 mL), then dried (MgSO₄), filtered and concentrated by rotaryevaporation. The crude product was purified by column chromatography,eluting with dichloromethane/methanol (90/10, v/v). Selected fractionscontaining the product were concentrated via rotary evaporation to give0.34 g of a yellow oil. To a solution of this oil in a mixture ofmethanol (9 mL) and water (1 mL) was added galactaric acid (141 mg). Themixture was stirred and heated until complete dissolution of thegalactaric acid and then concentrated by rotary evaporation to give anoil, which was triturated in a mixture of ethanol (1 mL) and isopropylacetate (5 mL). The resulting solid was filtered, washed with isopropylacetate, then diisopropyl ether and dried under vacuum at 40° C. to give0.4 g (56%) of an off-white solid.

Sample No. 8 exhibits a K_(i) of 56 nM. The low binding constantindicates that the compound exhibits good high-affinity binding tocertain CNS nicotinic receptors.

Example 9

Sample No. 9 is (S)-3-(phenoxyphenyl)-5-(pyrrolidin-2-ylethynyl)pyridinehemigalactarate, which was prepared in accordance with the followingtechniques:

3-Bromo-5-(phenoxyphenyl)pyridine

Under a nitrogen atmosphere, a mixture of 3,5-dibromopyridine (5.16 g,21.8 mmol), water (36.5 mL), toluene (145 mL), ethanol (36.5 mL),4-phenoxyphenylboronic acid (5.00 g, 23.3 mmol), sodium carbonate (4.9g, 47 mmol) and tetrakis(triphenylphosphine)palladium (1.25 g, 1.04mmol) was stirred and heated under reflux for 5 h. After cooling to roomtemperature, water (150 mL) was added and the aqueous phase separatedand extracted with ethyl acetate (3×100 mL). The combined organic phaseswere washed with water (50 mL), then dried (MgSO₄), treated with 3SBlack (decolorizing charcoal), filtered, and concentrated by rotaryevaporation. The residue was purified by column chromatography, elutingwith cyclohexane/ethyl acetate (90/10, v/v) to give 2.3 g (32%) of awhite solid, mp 109° C.

(S)-N-(tert-Butoxycarbonyl)-2-(5-(phenoxyphenyl)-3-pyridyl)ethynyl-1-pyrrolidine

Triethylamine (15 mL) was degassed by bubbling argon over a period of 30min. (S)-N-tert-(Butoxycarbonyl)-2-ethynyl-1-pyrrolidine (0.781 g, 4mmol), 3-bromo-5-phenoxypyridine (2.31 g, 8 mmol),tetrakis(triphenylphosphine)palladium (0.231 g, 0.2 mmol), palladium(II)acetate (0.045 g, 0.2 mmol) and copper (I) iodide (13.3 mg, 0.07 mmol)were added. The mixture was heated under reflux for 3 h, then cooled toroom temperature and concentrated by rotary evaporation. The residue wasdissolved in ethyl acetate (50 mL) and the organic phase washed withwater (2×25 mL), saturated bicarbonate aqueous solution (2×25 mL) andwater (25 mL), then dried (MgSO₄), filtered and concentrated by rotaryevaporation. The crude product was purified by column chromatography,eluting with ethyl acetate/cyclohexane (20/80, v/v). Selected fractionscontaining the product were concentrated via rotary evaporation to give0.9 g (51%) of an orange oil.

(S)-3-(Phenoxyphenyl)-5-(pyrrolidin-2-ylethynyl)pyridine hemigalactarate

An ice-cold stirred solution of(S)-N-(tert-butoxycarbonyl)-2-(5-(phenoxyphenyl)-3-pyridyl)ethynyl-1-pyrrolidine(900 mg, 2 mmol) in dichloromethane (16 mL) was treated withtrifluoroacetic acid (3.2 mL). The mixture was stirred for 30 min at0-5° C., then for 3 h at room temperature, and then it was concentratedon a rotary evaporator. To the oily residue was added water (25 mL) andthe pH was brought to 12 with 1N NaOH. The aqueous phase was extractedwith dichloromethane (3×25 mL). The combined organic phases were washedwith brine (5 mL), then dried (MgSO₄), filtered and concentrated byrotary evaporation. The crude product was purified by columnchromatography, eluting with dichloromethane/methanol (90/10, v/v).Selected fractions containing the product were concentrated via rotaryevaporation to give 0.5 g of a yellow oil. To a solution of the residuein a mixture of methanol (9 mL) and water (2 mL) was added galactaricacid (154 mg, 0.73 mmol). The mixture was stirred and heated untilcomplete dissolution of the galactaric acid, then was cooled to roomtemperature and concentrated by rotary evaporation to give an oil, whichwas triturated in a mixture of ethanol (2 mL) and isopropyl acetate (9mL). The resulting solid was filtered, washed with isopropyl acetate,then diisopropyl ether and dried under vacuum at 40° C. to afford 580 mg(64%) of an off-white solid.

Sample No. 9 exhibits a K_(i) of 530 nM. The low binding constantindicates that the compound exhibits good high-affinity binding tocertain CNS nicotinic receptors.

Example 10

Sample No. 10 is(S)-3-(4-methoxyphenoxy)-5-(pyrrolidin-2-ylethynyl)pyridinehemigalactarate, which was prepared in accordance with the followingtechniques:

3-Bromo-5-(4-methoxyphenoxy)pyridine

Under an argon atmosphere, a solution of 4-methoxyphenol (15.7 g, 0.126mol) in dimethylformamide (50 mL) was added slowly to a stirredsuspension sodium hydride (3.6 g of a 80% suspension in mineral oil,0.125 mol) in dimethylformamide (100 mL) at 3-7° C. The ice-bath wasremoved and the resulting mixture was stirred for 2 h at roomtemperature. A solution of 3,5-dibromopyridine (20 g, 0.083 mol) indimethylformamide (120 mL) was added to the mixture, which was thenheated to 100° C. for 36 h, then cooled to room temperature and pouredinto a mixture of water (500 mL) and ethyl acetate (500 mL). The aqueousphase was separated and extracted with ethyl acetate (2×100 mL). Thecombined organic phases were washed with water (3×100 mL) and then brine(100 mL), then dried (MgSO₄), filtered and concentrated by rotaryevaporation to give 22.5 g of an orange oil, which was purified bycolumn chromatography, with cyclohexane/ethyl acetate (95/5, v/v) aseluant. Selected fractions containing the product were concentrated viarotary evaporation to give 18.8 g (81%) of a colorless oil.

(S)-N-(tert-Butoxycarbonyl)-2-(5-(4-methoxyphenoxy)-3-pyridyl)ethynyl-1-pyrrolidine

Triethylamine (25 mL) was degassed by bubbling argon over a period of 30min. (S)-N-tert-Butoxycarbonyl-2-ethynyl-1-pyrrolidine (0.977 g, 5mmol), 3-bromo-5-(4-methoxyphenoxy)pyridine (2.1 g, 7.5 mmol),tetrakis(triphenylphosphine) palladium (0.289 g, 0.25 mmol),palladium(II) acetate (0.056 g, 0.25 mmol) and copper (I) iodide (20 mg,0.11 mmol) were added. The mixture was heated under reflux for 3 h, thenwas cooled to room temperature and concentrated by rotary evaporation.The residue was dissolved in ethyl acetate (50 mL) and the organic phasewashed with water (2×25 mL), saturated aqueous NaHCO₃ solution (2×25 mL)and water (25 mL), then dried (MgSO₄), filtered and concentrated byrotary evaporation. The crude product was purified by columnchromatography, eluting with ethyl acetate/cyclohexane (20/80, v/v).Selected fractions containing the product were concentrated via rotaryevaporation to give 0.95 (48%) of an orange oil.

(S)-3-(4-Methoxyphenoxy)-5-(pyrrolidin-2-ylethynyl)pyridinehemigalactarate

An ice-cold stirred solution of(S)-N-(tert-butoxycarbonyl)-2-(5-(4-methoxyphenoxy)-3-pyridyl)ethynyl-1-pyrrolidine(0.95 g, 2.41 mmol) in dichloromethane (19 mL) was treated withtrifluoroacetic acid (3.7 mL). The mixture was stirred for 30 min at0-5° C., then for 3 h at room temperature, and then it was concentratedon a rotary evaporator. To the oily residue was added water (10 mL) andthe pH was brought to 12 with 1N NaOH. The aqueous phase was extractedwith dichloromethane (3×25 mL). The combined organic phases were washedwith brine (5 mL), then dried (MgSO₄), filtered and concentrated byrotary evaporation. The crude product was purified by columnchromatography, eluting with dichloromethane/methanol (90/10, v/v).Selected fractions containing the product were concentrated via rotaryevaporation to give 0.45 g of a yellow oil. To a solution of the residuein a mixture of methanol (10 mL) and water (2 mL) was added galactaricacid (157 mg, 0.75 mmol). The mixture was stirred and heated untilcomplete dissolution of the galactaric acid, then was cooled to roomtemperature and concentrated by rotary evaporation to give an oil, whichwas triturated in a mixture of ethanol (2 mL) and isopropyl acetate (7mL). The resulting solid was filtered, washed with isopropyl acetate anddried under vacuum at 40° C. to afford 490 mg (51%) of an off-whitesolid.

Sample No. 10 exhibits a K_(i) of 33 nM. The low binding constantindicates that the compound exhibits good high-affinity binding tocertain CNS nicotinic receptors.

Example 11

Sample No. 11 is(S)-3-(4-hydroxyphenoxy)-5-(pyrrolidin-2-ylethynyl)pyridine, which wasprepared in accordance with the following techniques:

(S)-3-(4-Hydroxyphenoxy)-5-(pyrrolidin-2-ylethynyl)pyridine

A cold (−10° C.), stirred solution of(S)-N-(tert-butoxycarbonyl)-2-(5-(4-methoxyphenoxy)-3-pyridyl)ethynyl-1-pyrrolidine(1.1 g, 2.79 mmol) in dichloromethane (25 mL) was treated with 1Msolution of boron tribromide in dichloromethane (8.4 mL, 8.4 mmol). Themixture was stirred for 3 h at −10° C., then for 20 h at roomtemperature, and then water (20 mL) was added and the pH brought to 7-8with 1N NaOH. The aqueous phase was extracted with dichloromethane (3×50mL). The combined organic phases were washed with water (50 mL), thendried (MgSO₄), filtered and concentrated by rotary evaporation. Thecrude product was purified by column chromatography, eluting withdichloromethane/methanol (90/10, v/v). Selected fractions containing theproduct were concentrated via rotary evaporation to give 0.4 g of solid,which was recrystallized in isopropanol (3 mL) affording 250 mg (32%) ofan off-white solid (m.p. 164° C.).

Sample No. 11 exhibits a K_(i) of 2 nM. The low binding constantindicates that the compound exhibits good high-affinity binding tocertain CNS nicotinic receptors.

Example 12

Sample No. 12 is(S)-3-cyclopentyloxy-5-(pyrrolidin-2-ylethynyl)pyridine, which wasprepared in accordance with the following techniques:

3-Bromo-5-cyclopentyloxypyridine

To a mixture of 5-bromo-3-pyridinol (5.22 g, 30 mmol), toluene (180 mL),triphenylphosphine (11.8 g, 45 mmol) and cyclopentanol (4.12 mL, 45mmol) was slowly added diethyl azodicarboxylate (7.1 mL, 45 mmol). Themixture was heated at 90° C. for 20 h, then cooled to room temperature,washed with water (3×100 mL) and then brine (100 mL), then dried(MgSO₄), filtered and concentrated by rotary evaporation. The crude oilwas purified by column chromatography, eluting with ethylacetate/cyclohexane (10/90, v/v). Selected fractions containing theproduct were concentrated via rotary evaporation to give 6.5 g (89%) ofan orange oil.

(S)-N-(tert-Butoxycarbonyl)-2-(5-cyclopentyloxy-3-pyridyl)ethynyl-1-pyrrolidine

Triethylamine (25 mL) was degassed by bubbling argon over a period of 30min. (S)-N-tert-(Butoxycarbonyl)-2-ethynyl-1-pyrrolidine (0.976 g, 5.0mmol), 3-bromo-5-cyclopentyloxypyridine (1.82 g, 7.5 mmol),tetrakis(triphenylphosphine)palladium (0.289 g, 0.25 mmol),palladium(II) acetate (0.056 g, 0.25 mmol) and copper (I) iodide (21 mg,0.11 mmol) were added. The mixture was heated under reflux for 3 h, thencooled to room temperature and concentrated by rotary evaporation. Theresidue was dissolved in ethyl acetate (100 mL) and the organic phasewashed with water (3×50 mL), saturated aqueous NaHCO₃ solution (2×50mL), water (50 mL) and then brine (50 mL), then dried (MgSO₄), filteredand concentrated by rotary evaporation. The crude product was purifiedby column chromatography, eluting with ethyl acetate/cyclohexane (20/80,v/v). Selected fractions containing the product were concentrated viarotary evaporation to give 0.8 g (45%) of an orange oil.

(S)-3-Cyclopentyloxy-5-(pyrrolidin-2-ylethynyl)pyridine hemigalactarate

An ice-cold stirred solution of(S)-N-(tert-butoxycarbonyl)-2-(5-cyclopentyloxy-3-pyridyl)ethynyl-1-pyrrolidine(800 mg, 2 mmol) in dichloromethane (18 mL) was treated withtrifluoroacetic acid (3.46 mL). The mixture was stirred for 30 min at0-5° C., then for 3 h at room temperature, and then it was concentratedon a rotary evaporator. To the oily residue was added water (5 mL) andthe pH was brought to 8 with 1N NaOH. The aqueous phase was extractedwith dichloromethane (3×25 mL). The combined organic phases were washedwith brine (25 mL), then dried (MgSO₄), filtered and concentrated byrotary evaporation. The crude product was purified by columnchromatography, eluting with dichloromethane/methanol (90/10, v/v).Selected fractions containing the product were concentrated via rotaryevaporation to give 0.48 g of a yellow oil. To a solution of this oil ina mixture of methanol (7.5 mL) and water (1.5 mL) was added galactaricacid (190 mg, 0.9 mmol). The mixture was stirred and heated untilcomplete dissolution of the galactaric acid, then was cooled to roomtemperature and concentrated by rotary evaporation to give an oil, whichwas triturated in a mixture of ethanol (1.5 mL) and isopropyl acetate(10 mL). The resulting solid was filtered, washed with isopropyl acetateand dried under vacuum at 60° C. to afford 565 mg (70%) of a beigesolid.

Sample No. 12 exhibits a K_(i) of 6 nM. The low binding constantindicates that the compound exhibits good high-affinity binding tocertain CNS nicotinic receptors.

Example 13

Sample No. 13 is (S)-3-cyclohexyloxy-5-(pyrrolidin-2-ylethynyl)pyridine,which was prepared in accordance with the following techniques:

3-Bromo-5-cyclohexyloxypyridine

Under an argon atmosphere, sodium (750 mg, 31.75 mmol) was added torefluxing cyclohexanol (15 mL). The mixture was refluxed until completeconsumption of sodium. The remaining cyclohexanol was removed by astream of argon to give a white solid, which was dissolved inN-methyl-pyrrolidinone (16 mL). After addition of 3,5-dibromopyridine (3g, 12.66 mmol), the mixture was stirred and heated at 90° C. for 1 h,then cooled to room temperature, poured into cold (5° C.) water (60 mL),and extracted with diethyl ether (3×50 mL). The combined organic phaseswere washed with water (25 mL) and then brine (25 mL), then dried(MgSO₄), filtered and concentrated by rotary evaporation to give 6.2 gof an orange oil, which was purified by column chromatography, elutingwith cyclohexane/ethyl acetate (95/5, v/v). Selected fractionscontaining the product were concentrated via rotary evaporation to give1.6 g (50%) of a light-yellow oil.

(S)-N-(tert-Butoxycarbonyl)-2-(5-cyclohexyloxy-3-pyridyl)ethynyl-1-pyrrolidine

Triethylamine (25 mL) was degassed by bubbling argon over a period of 30min. (S)-N-tert-(Butoxycarbonyl)-2-ethynyl-1-pyrrolidine (0.976 g, 5mmol), 3-bromo-5-cyclohexyloxypyridine (1.92 g, 7.5 mmol),tetrakis(triphenylphosphine)palladium (0.289 g, 0.25 mmol),palladium(II) acetate (0.056 g, 0.25 mmol) and copper (I) iodide (21 mg,0.11 mmol) were added. The mixture was heated under reflux for 3 h, thencooled to room temperature and concentrated by rotary evaporation. Theresidue was dissolved in ethyl acetate (100 mL) and the organic phasewashed with water (2×50 mL), saturated aqueous NaHCO₃ solution (50 mL),water (2×50 mL) and brine (50 mL), then dried (MgSO₄), filtered andconcentrated by rotary evaporation. The crude product was purified bycolumn chromatography, eluting with ethyl acetate/cyclohexane (20/80,v/v). Selected fractions containing the product were concentrated viarotary evaporation to give 1.2 g (65%) of a yellow oil.

(S)-3-Cyclohexyloxy-5-(pyrrolidin-2-ylethynyl)pyridine hemigalactarate

An ice-cold stirred solution of(S)-N-(tert-butoxycarbonyl)-2-(5-cyclohexyloxy-3-pyridyl)ethynyl-1-pyrrolidine(1.2 g, 3.24 mmol) in dichloromethane (12.5 mL) was treated withtrifluoroacetic acid (2.5 mL). The mixture was stirred for 30 min at0-5° C., then for 3 h at room temperature, and then it was concentratedon a rotary evaporator. To the oily residue was added water (10 mL) andthe pH was brought to 12 with 1N NaOH. The aqueous phase was extractedwith dichloromethane (3×50 mL). The combined organic phases were washedwith brine (50 mL), then dried (MgSO₄), filtered and concentrated byrotary evaporation. The crude product was purified by columnchromatography, eluting with dichloromethane/methanol (95/5, v/v).Selected fractions containing the product were concentrated via rotaryevaporation to give 0.6 g of a yellow oil. To a solution of this oil ina mixture of methanol (10 mL) and water (2 mL) was added galactaric acid(233 mg, 1.11 mmol). The mixture was stirred and heated at 50° C. untilcomplete dissolution of the galactaric acid, then cooled to roomtemperature and concentrated by rotary evaporation to give an oil, whichwas triturated in a mixture of ethanol (2 mL) and isopropyl acetate (10mL). The resulting solid was filtered, washed with isopropyl acetate,then diisopropyloxide, and dried under vacuum at 60° C. to afford 0.66 g(54%) of a beige solid.

Sample No. 13 exhibits a K_(i) of 90 nM. The low binding constantindicates that the compound exhibits good high-affinity binding tocertain CNS nicotinic receptors.

Example 14

Sample No. 14 is(S)-3-(4-(pyrrolidine-1-sulfonyl)phenoxy)-5-(pyrrolidin-2-ylethynyl)pyridinehemigalactarate, which was prepared in accordance with the followingtechniques:

3-Bromo-5-(4-(pyrrolidine-1-sulfonyl)phenoxy)pyridine

A mixture of 5-bromo-3-pyridinol (2.61 g, 15 mmol), dimethylacetamide(50 mL), 1-((4-fluorophenyl)sulfonyl)pyrrolidine (5.8 g, 25 mmol) andpotassium carbonate (4.1 g, 30 mmol) was heated at 120° C. for 18 h,then cooled to room temperature and concentrated by rotary evaporation.The residue was dissolved in ethyl acetate (200 mL) and the organicphase washed with water (3×100 mL) and brine (100 mL), then dried(MgSO₄), filtered and concentrated by rotary evaporation. The crudeproduct was purified by column chromatography, eluting with ethylacetate/cyclohexane (20/80, v/v). Selected fractions containing theproduct were concentrated via rotary evaporation to give 3.4 g (59%) ofa red solid (m.p. 148° C.)

(S)-N-(tert-Butoxycarbonyl)-2-(5-(4-(pyrrolidine-1-sulfonyl)phenoxy)-3-pyridyl)ethynyl-1-pyrrolidine

Triethylamine (25 mL) was degassed by bubbling argon over a period of 30min. (S)-N-(tert-Butoxycarbonyl)-2-ethynyl-1-pyrrolidine (0.977 g, 5mmol), 3-bromo-5-[4-(pyrrolidine-1-sulfonyl)phenoxy]pyridine (2.87 g,7.5 mmol), tetrakis(triphenylphosphine)palladium (0.289 g, 0.25 mmol),palladium(II) acetate (0.056 g, 0.25 mmol) and copper (I) iodide (21 mg,0.11 mmol) were added. The mixture was heated under reflux for 3 h, thencooled to room temperature and concentrated by rotary evaporation. Theresidue was dissolved in ethyl acetate (100 mL) and the organic phasewashed with water (2×50 mL), saturated aqueous NaHCO₃ solution (2×50mL), water (2×50 mL) and brine (50 mL), then dried (MgSO₄), filtered andconcentrated by rotary evaporation. The crude product was purified bycolumn chromatography, eluting with ethyl acetate/cyclohexane (30/70,v/v). Selected fractions containing the product were concentrated viarotary evaporation to give 2 g (80%) of an orange oil.

(S)-3-(4-(Pyrrolidine-1-sulfonyl)phenoxy)-5-(pyrrolidin-2-ylethynyl)pyridinehemigalactarate

An ice-cold stirred solution of(S)-N-(tert-butoxycarbonyl)-2-(5-(4-(pyrrolidine-1-sulfonyl)phenoxy)-3-pyridyl)ethynyl-1-pyrrolidine(2 g, 4.02 mmol) in dichloromethane (15.5 mL) was treated withtrifluoroacetic acid (3.1 mL). The mixture was stirred for 30 min at0-5° C., then for 3 h at room temperature, and then it was concentratedon a rotary evaporator. To the oily residue was added water (10 mL) andthe pH was adjusted to 12 with 1N NaOH. The aqueous phase was extractedwith dichloromethane (3×50 mL). The combined organic phases were washedwith water (50 mL), then dried (MgSO₄), filtered and concentrated byrotary evaporation. The crude product was purified by columnchromatography, eluting with dichloromethane/methanol (95/5, v/v).Selected fractions containing the product were concentrated via rotaryevaporation to give 1.1 g of a yellow oil. To a solution of this oil ina mixture of methanol (10 mL) and water (2 mL) was added galactaric acid(280 mg, 1.38 mmol). The mixture was stirred and heated at 50° C. untilcomplete dissolution of the galactaric acid, then cooled to roomtemperature and concentrated by rotary evaporation to give an oil, whichwas triturated in a mixture of ethanol (2 mL) and isopropyl acetate (10mL). The resulting solid was filtered, washed with isopropyl acetate,then diisopropyl ether, and dried under vacuum at 60° C. to afford 1.2 g(59%) of a beige solid.

Sample No. 14 exhibits a K_(i) of 100 nM. The low binding constantindicates that the compound exhibits good high-affinity binding tocertain CNS nicotinic receptors.

Example 15

Sample No. 15 is (S)-3-(3-pyridyloxy)-5-(pyrrolidin-2-ylethynyl)pyridinehemigalactarate, which was prepared in accordance with the followingtechniques:

3-Bromo-5-(3-pyridyloxy)pyridine

To a solution of 3-pyridinol (4.32 g, 45 mmol) in dimethylformamide (50mL) was added sodium hydride (1.35 g of a 80% suspension in mineral oil,45 mmol). The mixture was stirred for 1 h at room temperature and3,5-dibromopyridine (5.92 g, 25 mmol) was added. The mixture was heatedfor 20 h at 130° C., then cooled to room temperature and poured intowater (300 mL). The aqueous phase was extracted with diethyl ether(3×100 mL) and the organic phase was washed with water (2×100 mL) andbrine (100 mL), then dried (MgSO₄), filtered and concentrated by rotaryevaporation. The crude product was purified by column chromatography,eluting with ethyl acetate/cyclohexane (30/70, v/v). Selected fractionscontaining the product were concentrated via rotary evaporation to give3.5 g (56%) of a yellow oil.

(S)-N-(tert-butoxycarbonyl)-2-(5-(3-pyridyloxy))-3-pyridyl)ethynyl-1-pyrrolidine

Triethylamine (25 mL) was degassed by bubbling argon over a period of 30min. (S)-N-(tert-butoxycarbonyl)-2-ethynyl-1-pyrrolidine (0.977 g, 5mmol), 3-bromo-5-(3-pyridyloxy)pyridine (1.88 g, 7.5 mmol),tetrakis(triphenylphosphine)palladium (0.289 g, 0.25 mmol),palladium(II) acetate (0.056 g, 0.25 mmol) and copper (I) iodide (21 mg,0.11 mmol) were added. The mixture was heated under reflux for 3 h, thencooled to room temperature and concentrated by rotary evaporation. Theresidue was dissolved in ethyl acetate (100 mL) and the organic phasewashed with water (2×50 mL), saturated aqueous NaHCO₃ solution (50 mL),water (50 mL) and brine (50 mL), then dried (MgSO₄), filtered andconcentrated by rotary evaporation. The crude product was purified bycolumn chromatography, eluting with ethyl acetate/cyclohexane (40/60,v/v). Selected fractions containing the product were concentrated viarotary evaporation to give 1.5 g (82%) of an orange oil.

(S)-3-(3-Pyridyloxy)-5-(pyrrolidin-2-ylethynyl)pyridine hemigalactarate

An ice-cold stirred solution of(S)-N-(tert-butoxycarbonyl)-2-(5-(3-pyridyloxy))-3-pyridyl)ethynyl-1-pyrrolidine(1.5 g, 4.1 mmol) in dichloromethane (16 mL) was treated withtrifluoroacetic acid (3.2 mL). The mixture was stirred for 30 min at0-5° C., then for 3 h at room temperature, and then it was concentratedon a rotary evaporator. To the oily residue was added water (10 mL) andthe pH was brought to 12 with 1N NaOH. The aqueous phase was extractedwith dichloromethane (3 times 50 mL). The combined organic phases werewashed with water (50 mL) and then brine (50 mL), then dried (MgSO₄),filtered and concentrated by rotary evaporation. The crude product waspurified by column chromatography, eluting with dichloromethane/methanol(95/5, v/v). Selected fractions containing the product were concentratedvia rotary evaporation to give 620 mg of a yellow oil. To a solution ofthis oil in a mixture of methanol (10 mL) and water (2 mL) was addedgalactaric acid (245 mg, 1.17 mmol). The mixture was stirred and heatedat 50° C. until complete dissolution of the galactaric acid, then cooledto room temperature and concentrated by rotary evaporation to give anoil, which was triturated in a mixture of ethanol (2 mL) and isopropylacetate (10 mL). The resulting solid was filtered, washed with isopropylacetate (2 times 5 mL), then diisopropyl oxide, and dried under vacuumat 60° C. to afford 0.75 g (49%) of a cream solid.

Sample No. 15 exhibits a K_(i) of 13 nM. The low binding constantindicates that the compound exhibits good high-affinity binding tocertain CNS nicotinic receptors.

Example 16

Sample No. 16 is(S)-3-(pyrrolidin-2-ylethynyl)-5-(tetrahydropyran-4-yloxy)pyridinehemigalactarate, which was prepared in accordance with the followingtechniques:

3-Bromo-5-(tetrahydropyran-4-yloxy)pyridine

To a mixture of 5-bromo-3-pyridinol (5.22 g, 30 mmol), toluene (150 mL),triphenylphosphine (11.8 g, 45 mmol) and tetrahydropyran-4-ol (4.7 g, 45mmol) was slowly added diethyl azodicarboxylate (7.1 mL, 45 mmol). Themixture was heated at reflux for 20 h, then cooled to room temperature,washed with water (3×100 mL) and then brine (100 mL), then dried(MgSO₄), filtered and concentrated by rotary evaporation. The crude oilwas treated with diisopropyloxide (50 mL) and the solid thus obtainedwas filtered and washed with diisopropyloxide (20 mL). The combinedfiltrates were concentrated by rotary evaporation and purified by columnchromatography on silica gel, eluting with ethyl acetate/cyclohexane(20/80, v/v). Selected fractions containing the product wereconcentrated via rotary evaporation to give 5 g (65%) of a yellow oil.

(S)-N-(tert-Butoxycarbonyl)-2-((5-(tetrahydropyran-4-yloxy))-3-pyridyl)ethynyl-1-pyrrolidine

Triethylamine (25 mL) was degassed by bubbling argon over a period of 30min. (S)-N-(tert-Butoxycarbonyl)-2-ethynyl-1-pyrrolidine (0.977 g, 5mmol), 3-bromo-5-(tetrahydropyran-4-yloxy)pyridine (1.94 g, 7.5 mmol),tetrakis(triphenylphosphine)palladium (0.289 g, 0.25 mmol),palladium(II) acetate (0.056 g, 0.25 mmol) and copper (I) iodide (21 mg,0.11 mmol) were added. The mixture was heated under reflux for 3 h, thencooled to room temperature and concentrated by rotary evaporation. Theresidue was dissolved in ethyl acetate (100 mL) and the organic phasewashed with water (2×50 mL), saturated aqueous NaHCO₃ solution (50 mL),water (50 mL) and brine (50 mL), then dried (MgSO₄), filtered andconcentrated by rotary evaporation. The crude product was purified bycolumn chromatography, eluting with ethyl acetate/cyclohexane (40/60,v/v). Selected fractions containing the product were concentrated viarotary evaporation to give 1.5 g (81%) of an orange oil.

(S)-3-(Pyrrolidin-2-ylethynyl)-5-(tetrahydropyran-4-yloxy)pyridinehemigalactarate

An ice-cold stirred solution of(S)-N-(tert-butoxycarbonyl)-2-((5-(tetrahydropyran-4-yloxy))-3-pyridyl)ethynyl-1-pyrrolidine(1.5 g, 4.0 mmol) in dichloromethane (15.5 mL) was treated withtrifluoroacetic acid (3.1 mL). The mixture was stirred for 30 min at0-5° C., then for 3 h at room temperature, and then it was concentratedon a rotary evaporator. To the oily residue was added water (10 mL) andthe pH was brought to 12 with 1N NaOH. The aqueous phase was extractedwith dichloromethane (3×50 mL). The combined organic phases were washedwith water (50 mL) and then brine (50 mL), then dried (MgSO₄), filteredand concentrated by rotary evaporation. The crude product was purifiedby column chromatography, eluting with dichloromethane/methanol (95/5,v/v). Selected fractions containing the product were concentrated viarotary evaporation to give 0.88 g of a yellow oil. To a solution of theresidue in a mixture of methanol (10 mL) and water (2 mL) was addedgalactaric acid (339 mg, 1.6 mmol). The mixture was stirred and heatedat 50° C. until complete dissolution of the galactaric acid, then cooledto room temperature and concentrated by rotary evaporation to give anoil, which was triturated in a mixture of ethanol (3 mL) and isopropylacetate (10 mL). The resulting solid was filtered, washed with isopropylacetate (2×5 mL), then diisopropyl ether, and dried under vacuum at 60°C. to afford 0.98 g (64%) of a cream solid.

Sample No. 16 exhibits a K_(i) of 7 nM. The low binding constantindicates that the compound exhibits good high-affinity binding tocertain CNS nicotinic receptors.

Example 17

Sample No. 17 is(S)-3-(3,5-dihydroxy)phenoxy-5-(pyrrolidin-2-ylethynyl)pyridine, whichwas prepared in accordance with the following techniques:

3-Bromo-5-(3,5-Dimethoxyphenoxy)pyridine

Under an argon atmosphere, a solution of 3,5-dimethoxyphenol (6.94 g, 45mmol) in dimethylformamide (30 mL) was added slowly to a stirredsuspension of sodium hydride (1.44 g of a 75% suspension in mineral oil,0.045 mol) in dimethylformamide (30 mL) at 0-5° C. The icebath wasremoved and the resulting mixture was stirred for 2.5 h at roomtemperature. 3,5-Dibromopyridine (7.11 g, 0.03 mol) was added to themixture, which was then heated to 100° C. for 72 h, then the mixture wascooled to room temperature and successively washed with water (100 mL)and 5 N NaOH solution (10 mL). The mixture was extracted with diethylether (3×50 mL). The combined organic phases were dried (MgSO₄),filtered and concentrated by rotary evaporation to give 9.2 g of a whitesolid, which was purified by column chromatography, eluting withcyclohexane/ethyl acetate (90/10, v/v). Selected fractions containingthe product were concentrated via rotary evaporation to give 2.5 g (29%)of a yellow oil.

(S)-(N-tert-Butoxycarbonyl)-2-(5-(3,5-Dimethoxy)phenoxy-3-pyridyl)ethynyl-1-pyrrolidine

Triethylamine (50 mL) was degassed by bubbling argon over a period of 30min. (S)-N-(tert-Butoxycarbonyl)-2-ethynyl-1-pyrrolidine (1.96 g, 10mmol), 3-bromo-5-(3,5-dimethoxyphenoxy)pyridine (4.8 g, 13.93 mmol),tetrakis(triphenylphosphine)palladium (0.578 g, 0.5 mmol), palladium(II)acetate (0.112 g, 0.5 mmol) and copper (I) iodide (42 mg, 0.22 mmol)were added. The mixture was heated under reflux for 3 h, then cooled toroom temperature and concentrated by rotary evaporation. The residue wasdissolved in ethyl acetate (150 mL) and the organic phase washed withwater (2×100 mL), saturated aqueous NaHCO₃ solution (100 mL) and water(100 mL), then dried (MgSO₄), filtered and concentrated by rotaryevaporation. The crude product was purified by column chromatography,eluting with ethyl acetate/cyclohexane (20/80, v/v). Selected fractionscontaining the product were concentrated via rotary evaporation to give1.6 g (38%) of an orange oil.

(S)-3-(3,5-Dihydroxy)phenoxy-5-(pyrrolidin-2-ylethynyl)pyridine

A stirred solution of(S)-N-(tert-butoxycarbonyl)-2-(5-(3,5-dimethoxy)phenoxy-3-pyridyl)ethynyl-1-pyrrolidine(1.1 g, 2.59 mmol) in dichloromethane (30 mL) was treated with 1Msolution of boron tribromide in dichloromethane (10.5 mL, 10.5 mmol).The mixture was stirred for 20 h at room temperature and thenconcentrated by rotary evaporation. Water (10 mL) was added to theresidue, then the pH was brought to 8 with saturated aqueous NaHCO₃solution and the solution stirred for 30 min at room temperature. Theinsoluble product was separated by filtration, washed with water (3×20mL) and dissolved in methanol-dichloromethane (20/80, v/v), then dried(MgSO₄, filtered and concentrated by rotary evaporation. The crudeproduct was purified by column chromatography, eluting withdichloromethane/methanol (80/20, v/v). Selected fractions containing theproduct were concentrated via rotary evaporation to give a solid, whichwas recrystallized from isopropanol (3 mL), affording 210 mg (32%) of abeige solid (m.p. 228° C.)

Sample No. 17 exhibits a K_(i) of 3 nM. The low binding constantindicates that the compound exhibits good high-affinity binding tocertain CNS nicotinic receptors.

Example 18

Sample No. 18 is(E)-(S)-3-(4-hydroxyphenoxy)-5-(pyrrolidin-2-ylvinyl)pyridine, which wasprepared in accordance with the following techniques:

(S)-3-(4-Hydroxyphenoxy)-5-(1-bromo-2-pyrrolidin-2-ylvinyl)pyridine

A stirred solution of(S)-N-(tert-butoxycarbonyl)-2-(5-(4-methoxyphenoxy)-3-pyridyl)ethynyl-1-pyrrolidine(1.1 g, 2.79 mmol) in hydrobromic acid (30 mL of a 48% aqueous solution)was heated under reflux for 10 h, then was stirred for 20 h at roomtemperature and concentrated by rotary evaporation. The residue wasdissolved in water (10 mL) and the pH brought to 11 with 1N NaOH. Theaqueous phase was extracted with dichloromethane (3×50 mL). The combinedorganic phases were washed with water (25 mL), then dried (MgSO₄),filtered and concentrated by rotary evaporation. The crude product waspurified by column chromatography, eluting with dichloromethane/methanol(90/10, v/v). Selected fractions containing the product wereconcentrated via rotary evaporation to give 0.84 g (98%) of an orangeoil.

(S)-N-(tert-Butoxycarbonyl)-(1-bromo-2-(5-(4-hydroxyphenoxy)-3-pyridyl)vinyl)-1-pyrrolidine

To a stirred solution of(S)-3-(4-hydroxyphenoxy)-5-(1-bromo-2-pyrrolidin-2-ylvinyl)pyridine indioxane (15 mL) were added water (15 mL) and sodium bicarbonate (375 mg,4.43 mmol). The mixture was stirred until homogenous andbis(1,1-dimethylethyl)dicarbonate (488 mg, 2.21 mmol) was added. Thesolution was stirred at room temperature for 20 h, then brought to pH 4by addition of 1N solution of hydrochloric acid and extracted by ethylacetate (3×50 mL). The combined organic phases were washed with water(50 mL), then dried (MgSO₄), filtered and concentrated by rotaryevaporation to give 1 g of an orange oil.

(E)-(S)-N-(tert-Butoxycarbonyl)-2-(5-(4-hydroxyphenoxy)-3-pyridyl)vinyl-1-pyrrolidine

To a cold (−78° C.) stirred solution of(S)-N-(tert-butoxycarbonyl)-(1-bromo-2-(5-(4-hydroxyphenoxy)-3-pyridyl)vinyl)-1-pyrrolidine(1 g, 2.17 mmol) in tetrahydrofuran (20 mL) was added dropwise butyllithium (3 mL of a 1.6 M solution in hexane, 4.77 mmol). The resultingmixture was stirred at −78° C. for 2 h, then a saturated solution ofammonium chloride was added dropwise and the pH brought to 4 by additionof a 1N solution of hydrochloric acid. The aqueous phase was extractedwith ethyl acetate (3×25 mL). The combined organic phases were dried(MgSO₄), filtered and concentrated by rotary evaporation to give 0.8 g(96%) of an orange oil.

(E)-(S)-3-(4-Hydroxyphenoxy)-5-(pyrrolidin-2-ylvinyl)pyridinehemigalactarate

An ice-cold stirred solution of(E,S)-N-(tert-butoxycarbonyl)-2-(5-(4-hydroxyphenoxy)-3-pyridyl)vinyl-1-pyrrolidine(0.8 g, 2.09 mmol) in dichloromethane (16 mL) was treated withtrifluoroacetic acid (3.22 mL). The mixture was stirred for 30 min at0-5° C., then for 3 h at room temperature, and then it was concentratedon a rotary evaporator. To the oily residue was added water (10 mL) andthe pH was brought to 8 with 1N NaOH. The aqueous phase was extractedwith dichloromethane (2×75 mL). The combined organic phases were washedwith water (50 mL), then dried (MgSO₄), filtered and concentrated byrotary evaporation. The crude product was purified by columnchromatography, eluting with dichloromethane/methanol (90/10, v/v).Selected fractions containing the product were concentrated via rotaryevaporation to give 0.14 g of an orange oil, which was dissolved in amixture of methanol (5 mL) and water (1 mL) and galactaric acid (52 mg,0.25 mmol) was added. The mixture was stirred and heated until completedissolution of the galactaric acid, then cooled to room temperature andconcentrated by rotary evaporation to give an oil, which was trituratedin isopropyl acetate. The resulting solid was filtered and dried undervacuum at 40° C. to afford 178 mg (22%) of a red solid.

Sample No. 18 exhibits a K_(i) of 20 nM. The low binding constantindicates that the compound exhibits good high-affinity binding tocertain CNS nicotinic receptors.

Example 19

Sample No. 19 is (E,S)-3-cyclopentyloxy-5-(pyrrolidin-2-ylvinyl)pyridinehemigalactarate, which was prepared in accordance with the followingtechniques:

(S)-N-(tert-Butoxycarbonyl)-2-vinyl-1-pyrrolidine

A suspension of Lindlar catalyst (0.1 g) in a solution of(S)-N-(tert-butoxycarbonyl)-2-ethynyl-1-pyrrolidine (1.95 g, 10 mmol) inethanol (20 mL) was shaken under a hydrogen atmosphere (1 bar) at roomtemperature for 3 h. The catalyst was removed by filtration and thefiltrate was concentrated by rotary evaporation to give 1.98 g of ayellow oil.

(S)-N-(tert-Butoxycarbonyl)-2-(5-cyclopentyloxy-3-pyridyl)vinyl-1-pyrrolidine

A mixture of 3-bromo-5-cyclopentyloxypyridine (1.21 g, 5 mmol),(S)-N-(tert-butoxycarbonyl)-2-vinyl-1-pyrrolidine (1.25 g, 6 mmol),palladium acetate (112 mg, 0.5 mmol), diisopropylethylamine (6.9 mL, 40mmol) and lithium chloride (636 mg, 15 mmol) in dimethylformamide (15mL) was heated at 110° C. for 4 h, then stirred at room temperature for2 h and concentrated by rotary evaporation. The residue was dissolved inethyl acetate (100 mL), washed with water (3×50 mL) and then brine (50mL), then dried (MgSO₄), filtered and concentrated by rotaryevaporation. The crude product was purified by column chromatography,eluting with cyclohexane/ethyl acetate (80/20, v/v). Selected fractionscontaining the product were concentrated via rotary evaporation to give0.7 g (39%) of an orange oil.

(E,S)-3-Cyclopentyloxy-5-(pyrrolidin-2-ylvinyl)pyridine hemigalactarate

An ice-cold stirred solution of(S)-N-(tert-butoxycarbonyl)-2-(5-cyclopentyloxy-3-pyridyl)vinyl-1-pyrrolidine(0.7 g, 1.76 mmol, 90% purity) in dichloromethane (7 mL) was treatedwith trifluoroacetic acid (1.36 mL). The mixture was stirred for 30 minat 0° C., then for 3 h at room temperature, and concentrated by rotaryevaporation. To the oily residue was added water (5 mL) and the pH wasbrought to 12 with 1N NaOH. The aqueous phase was extracted withdichloromethane (3×50 mL). The combined organic phases were washed withwater (50 mL) and then brine (50 mL), then dried (MgSO₄), filtered andconcentrated by rotary evaporation. The crude product was purified bycolumn chromatography, eluting with dichloromethane/methanol (90/10,v/v). Selected fractions containing the product were concentrated viarotary evaporation to give 0.26 g of an orange oil. To a solution ofthis oil in a mixture of methanol (5 mL) and water (1 mL) was addedgalactaric acid (105 mg, 0.5 mmol). The mixture was stirred and heateduntil complete dissolution of the galactaric acid, then cooled to roomtemperature and concentrated by rotary evaporation to give an oil, whichwas triturated in a mixture of ethanol (1 mL) and isopropyl acetate (5mL). The resulting solid was filtered, washed with isopropyl acetatethen diisopropyl oxide and dried under vacuum at 60° C. to afford 260 mg(40%) of a beige solid.

Sample No. 19 exhibits a K_(i) of 51 nM. The low binding constantindicates that the compound exhibits good high-affinity binding tocertain CNS nicotinic receptors.

The foregoing is illustrative of the present invention and is not to beconstrued as limiting thereof. The invention is defined by the followingclaims, with equivalents of the claims to be included therein.

1. A compound of the formula:

where each of X and X′ are individually nitrogen, nitrogen bonded to oxygen or carbon bonded to a substituent species characterized as having a sigma m value between about −0.3 and about 0.75; m is an integer and n is an integer such that the sum of m plus n is 0, 1, 2 or 3; E, E^(I), E^(II) and E^(III) individually represent hydrogen or a suitable non-hydrogen substituent; and Q is selected from:

where Z′ represents hydrogen or lower alkyl acyl, alkoxycarbonyl, or aryloxycarbonyl; Z″ is hydrogen or lower alkyl; and Z′″ is a non-hydrogen substituent; the dotted line indicates a carbon-carbon single bond or a carbon-carbon double bond; p is 0, 1 or 2; q is 0, 1, 2 or 3; and j is an integer from 0 to
 3. 